US20210188787A1 - Dota compounds and uses thereof - Google Patents
Dota compounds and uses thereof Download PDFInfo
- Publication number
- US20210188787A1 US20210188787A1 US17/251,038 US201917251038A US2021188787A1 US 20210188787 A1 US20210188787 A1 US 20210188787A1 US 201917251038 A US201917251038 A US 201917251038A US 2021188787 A1 US2021188787 A1 US 2021188787A1
- Authority
- US
- United States
- Prior art keywords
- unsubstituted
- substituted
- compound
- salt
- type
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 178
- 238000000034 method Methods 0.000 claims abstract description 41
- 238000001514 detection method Methods 0.000 claims abstract description 31
- 239000012491 analyte Substances 0.000 claims abstract description 30
- 238000003384 imaging method Methods 0.000 claims abstract description 17
- 102000003992 Peroxidases Human genes 0.000 claims abstract description 15
- 238000004949 mass spectrometry Methods 0.000 claims abstract description 14
- 108040007629 peroxidase activity proteins Proteins 0.000 claims abstract description 13
- 238000000386 microscopy Methods 0.000 claims abstract description 11
- 102000004169 proteins and genes Human genes 0.000 claims abstract description 6
- 108090000623 proteins and genes Proteins 0.000 claims abstract description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 104
- 150000003839 salts Chemical class 0.000 claims description 93
- 125000000304 alkynyl group Chemical group 0.000 claims description 82
- 125000000623 heterocyclic group Chemical group 0.000 claims description 81
- 125000003342 alkenyl group Chemical group 0.000 claims description 78
- 125000004452 carbocyclyl group Chemical group 0.000 claims description 74
- 229910052739 hydrogen Inorganic materials 0.000 claims description 73
- 239000001257 hydrogen Substances 0.000 claims description 73
- 150000004697 chelate complex Chemical class 0.000 claims description 62
- 125000003118 aryl group Chemical group 0.000 claims description 61
- 125000001072 heteroaryl group Chemical group 0.000 claims description 58
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 45
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 44
- 125000004404 heteroalkyl group Chemical group 0.000 claims description 38
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 36
- 229910052757 nitrogen Inorganic materials 0.000 claims description 31
- 125000002252 acyl group Chemical group 0.000 claims description 30
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 30
- 229910052736 halogen Inorganic materials 0.000 claims description 29
- 150000002367 halogens Chemical group 0.000 claims description 29
- 125000002947 alkylene group Chemical group 0.000 claims description 26
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 26
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 25
- 229910052717 sulfur Inorganic materials 0.000 claims description 25
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 24
- 229910052760 oxygen Inorganic materials 0.000 claims description 23
- 102000004190 Enzymes Human genes 0.000 claims description 19
- 108090000790 Enzymes Proteins 0.000 claims description 19
- 229910052751 metal Inorganic materials 0.000 claims description 18
- 239000002184 metal Substances 0.000 claims description 18
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 18
- 125000004450 alkenylene group Chemical group 0.000 claims description 16
- 239000012472 biological sample Substances 0.000 claims description 16
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 13
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims description 13
- 229910052727 yttrium Inorganic materials 0.000 claims description 13
- VWQVUPCCIRVNHF-UHFFFAOYSA-N yttrium atom Chemical compound [Y] VWQVUPCCIRVNHF-UHFFFAOYSA-N 0.000 claims description 13
- 125000000732 arylene group Chemical group 0.000 claims description 11
- 125000005549 heteroarylene group Chemical group 0.000 claims description 8
- 229910052777 Praseodymium Inorganic materials 0.000 claims description 7
- PUDIUYLPXJFUGB-UHFFFAOYSA-N praseodymium atom Chemical compound [Pr] PUDIUYLPXJFUGB-UHFFFAOYSA-N 0.000 claims description 7
- 125000004419 alkynylene group Chemical group 0.000 claims description 6
- 229910052747 lanthanoid Inorganic materials 0.000 claims description 6
- 150000002602 lanthanoids Chemical class 0.000 claims description 6
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 5
- ZSLUVFAKFWKJRC-IGMARMGPSA-N 232Th Chemical compound [232Th] ZSLUVFAKFWKJRC-IGMARMGPSA-N 0.000 claims description 4
- 229910052765 Lutetium Inorganic materials 0.000 claims description 4
- 229910052776 Thorium Inorganic materials 0.000 claims description 4
- 229910052767 actinium Inorganic materials 0.000 claims description 4
- QQINRWTZWGJFDB-UHFFFAOYSA-N actinium atom Chemical compound [Ac] QQINRWTZWGJFDB-UHFFFAOYSA-N 0.000 claims description 4
- 230000027455 binding Effects 0.000 claims description 4
- 229910052797 bismuth Inorganic materials 0.000 claims description 4
- JCXGWMGPZLAOME-UHFFFAOYSA-N bismuth atom Chemical compound [Bi] JCXGWMGPZLAOME-UHFFFAOYSA-N 0.000 claims description 4
- 229910052793 cadmium Inorganic materials 0.000 claims description 4
- BDOSMKKIYDKNTQ-UHFFFAOYSA-N cadmium atom Chemical compound [Cd] BDOSMKKIYDKNTQ-UHFFFAOYSA-N 0.000 claims description 4
- OHSVLFRHMCKCQY-UHFFFAOYSA-N lutetium atom Chemical compound [Lu] OHSVLFRHMCKCQY-UHFFFAOYSA-N 0.000 claims description 4
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 claims description 4
- 229910052753 mercury Inorganic materials 0.000 claims description 4
- 229910052712 strontium Inorganic materials 0.000 claims description 4
- CIOAGBVUUVVLOB-UHFFFAOYSA-N strontium atom Chemical compound [Sr] CIOAGBVUUVVLOB-UHFFFAOYSA-N 0.000 claims description 4
- 150000002431 hydrogen Chemical group 0.000 claims 7
- WDLRUFUQRNWCPK-UHFFFAOYSA-N Tetraxetan Chemical compound OC(=O)CN1CCN(CC(O)=O)CCN(CC(O)=O)CCN(CC(O)=O)CC1 WDLRUFUQRNWCPK-UHFFFAOYSA-N 0.000 abstract description 23
- 230000008021 deposition Effects 0.000 abstract description 12
- 239000003248 enzyme activator Substances 0.000 abstract description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 323
- -1 tyramides Chemical class 0.000 description 144
- 125000004432 carbon atom Chemical group C* 0.000 description 95
- 125000005842 heteroatom Chemical group 0.000 description 86
- 238000005406 washing Methods 0.000 description 66
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 50
- 239000008367 deionised water Substances 0.000 description 40
- 229910021641 deionized water Inorganic materials 0.000 description 40
- 0 *O*C1=C([6*])C([5*])=C([4*]C(=C)C([3*])[2*][1*]C)C([8*])=C1[7*] Chemical compound *O*C1=C([6*])C([5*])=C([4*]C(=C)C([3*])[2*][1*]C)C([8*])=C1[7*] 0.000 description 34
- 239000012453 solvate Substances 0.000 description 28
- 125000001424 substituent group Chemical group 0.000 description 27
- 238000003556 assay Methods 0.000 description 24
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 23
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 21
- 239000013078 crystal Substances 0.000 description 21
- 229920000642 polymer Polymers 0.000 description 21
- 239000001301 oxygen Substances 0.000 description 18
- 239000013522 chelant Chemical class 0.000 description 17
- 239000011593 sulfur Substances 0.000 description 17
- 229920006395 saturated elastomer Polymers 0.000 description 15
- 210000001519 tissue Anatomy 0.000 description 15
- WZUVPPKBWHMQCE-UHFFFAOYSA-N Haematoxylin Chemical compound C12=CC(O)=C(O)C=C2CC2(O)C1C1=CC=C(O)C(O)=C1OC2 WZUVPPKBWHMQCE-UHFFFAOYSA-N 0.000 description 14
- 125000004122 cyclic group Chemical group 0.000 description 14
- 125000000753 cycloalkyl group Chemical group 0.000 description 14
- 125000006708 (C5-C14) heteroaryl group Chemical group 0.000 description 13
- 241000283707 Capra Species 0.000 description 12
- 102000008730 Nestin Human genes 0.000 description 12
- 108010088225 Nestin Proteins 0.000 description 12
- 239000000203 mixture Substances 0.000 description 12
- 229910021645 metal ion Inorganic materials 0.000 description 11
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 10
- 210000005055 nestin Anatomy 0.000 description 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 10
- 229910001868 water Inorganic materials 0.000 description 10
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 description 9
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 description 8
- 125000001188 haloalkyl group Chemical group 0.000 description 8
- 125000004474 heteroalkylene group Chemical group 0.000 description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 8
- 150000003254 radicals Chemical class 0.000 description 8
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 7
- 125000005915 C6-C14 aryl group Chemical group 0.000 description 7
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 7
- 241000283973 Oryctolagus cuniculus Species 0.000 description 7
- 125000004429 atom Chemical group 0.000 description 7
- 229910052799 carbon Inorganic materials 0.000 description 7
- HSTOKWSFWGCZMH-UHFFFAOYSA-N 3,3'-diaminobenzidine Chemical compound C1=C(N)C(N)=CC=C1C1=CC=C(N)C(N)=C1 HSTOKWSFWGCZMH-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 6
- 239000002738 chelating agent Substances 0.000 description 6
- GTCAXTIRRLKXRU-UHFFFAOYSA-N methyl carbamate Chemical compound COC(N)=O GTCAXTIRRLKXRU-UHFFFAOYSA-N 0.000 description 6
- 150000002978 peroxides Chemical class 0.000 description 6
- 125000003367 polycyclic group Chemical group 0.000 description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 6
- 125000006714 (C3-C10) heterocyclyl group Chemical group 0.000 description 5
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 5
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 5
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 description 5
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 5
- 125000002015 acyclic group Chemical group 0.000 description 5
- 125000003277 amino group Chemical group 0.000 description 5
- 150000001721 carbon Chemical group 0.000 description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 5
- 210000004027 cell Anatomy 0.000 description 5
- 125000002950 monocyclic group Chemical group 0.000 description 5
- 125000006574 non-aromatic ring group Chemical group 0.000 description 5
- XSXHWVKGUXMUQE-UHFFFAOYSA-N osmium dioxide Inorganic materials O=[Os]=O XSXHWVKGUXMUQE-UHFFFAOYSA-N 0.000 description 5
- 125000006239 protecting group Chemical group 0.000 description 5
- 239000012048 reactive intermediate Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 5
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 5
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 5
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 5
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 description 4
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 description 4
- LJCZNYWLQZZIOS-UHFFFAOYSA-N 2,2,2-trichlorethoxycarbonyl chloride Chemical compound ClC(=O)OCC(Cl)(Cl)Cl LJCZNYWLQZZIOS-UHFFFAOYSA-N 0.000 description 4
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 4
- 125000006163 5-membered heteroaryl group Chemical group 0.000 description 4
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical class CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 4
- 125000000041 C6-C10 aryl group Chemical group 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 4
- 229910002651 NO3 Inorganic materials 0.000 description 4
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 4
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 4
- 229910019142 PO4 Inorganic materials 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 4
- 230000003321 amplification Effects 0.000 description 4
- 125000003710 aryl alkyl group Chemical group 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 4
- PUJDIJCNWFYVJX-UHFFFAOYSA-N benzyl carbamate Chemical compound NC(=O)OCC1=CC=CC=C1 PUJDIJCNWFYVJX-UHFFFAOYSA-N 0.000 description 4
- 125000002619 bicyclic group Chemical group 0.000 description 4
- 125000004092 methylthiomethyl group Chemical group [H]C([H])([H])SC([H])([H])* 0.000 description 4
- 238000003199 nucleic acid amplification method Methods 0.000 description 4
- 210000002966 serum Anatomy 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 4
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 3
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 description 3
- 125000006706 (C3-C6) carbocyclyl group Chemical group 0.000 description 3
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 3
- 125000006704 (C5-C6) cycloalkyl group Chemical group 0.000 description 3
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 3
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 3
- 125000006164 6-membered heteroaryl group Chemical group 0.000 description 3
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 3
- 102100023974 Keratin, type II cytoskeletal 7 Human genes 0.000 description 3
- 108010070507 Keratin-7 Proteins 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 229910006069 SO3H Inorganic materials 0.000 description 3
- 239000007983 Tris buffer Substances 0.000 description 3
- 125000001931 aliphatic group Chemical group 0.000 description 3
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 125000000129 anionic group Chemical group 0.000 description 3
- 125000004104 aryloxy group Chemical group 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 125000001246 bromo group Chemical group Br* 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 125000001309 chloro group Chemical group Cl* 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 230000001419 dependent effect Effects 0.000 description 3
- 150000002148 esters Chemical group 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 229940050410 gluconate Drugs 0.000 description 3
- 125000005843 halogen group Chemical group 0.000 description 3
- 150000004677 hydrates Chemical class 0.000 description 3
- 150000002430 hydrocarbons Chemical group 0.000 description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 3
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 210000002826 placenta Anatomy 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 125000006853 reporter group Chemical group 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 229940095064 tartrate Drugs 0.000 description 3
- 238000003419 tautomerization reaction Methods 0.000 description 3
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical compound C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 3
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 2
- WTKQMHWYSBWUBE-UHFFFAOYSA-N (3-nitropyridin-2-yl) thiohypochlorite Chemical compound [O-][N+](=O)C1=CC=CN=C1SCl WTKQMHWYSBWUBE-UHFFFAOYSA-N 0.000 description 2
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 2
- 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 description 2
- 125000004972 1-butynyl group Chemical group [H]C([H])([H])C([H])([H])C#C* 0.000 description 2
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 2
- 125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([H])([H])* 0.000 description 2
- LSBDFXRDZJMBSC-UHFFFAOYSA-N 2-phenylacetamide Chemical class NC(=O)CC1=CC=CC=C1 LSBDFXRDZJMBSC-UHFFFAOYSA-N 0.000 description 2
- LDZNCSVWVMBVST-UHFFFAOYSA-N 2-trimethylsilylethyl hydrogen carbonate Chemical compound C[Si](C)(C)CCOC(O)=O LDZNCSVWVMBVST-UHFFFAOYSA-N 0.000 description 2
- 125000002774 3,4-dimethoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C(OC([H])([H])[H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 2
- XMIIGOLPHOKFCH-UHFFFAOYSA-M 3-phenylpropionate Chemical compound [O-]C(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-M 0.000 description 2
- PXACTUVBBMDKRW-UHFFFAOYSA-M 4-bromobenzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=C(Br)C=C1 PXACTUVBBMDKRW-UHFFFAOYSA-M 0.000 description 2
- JOOXCMJARBKPKM-UHFFFAOYSA-M 4-oxopentanoate Chemical compound CC(=O)CCC([O-])=O JOOXCMJARBKPKM-UHFFFAOYSA-M 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 2
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 2
- FOWGHKUGYIXBQM-PNVBZASYSA-N CC(C)/C=C/C(C)C.CC(C)CCC(C)C.CC(C)CCNC(C)C Chemical compound CC(C)/C=C/C(C)C.CC(C)CCC(C)C.CC(C)CCNC(C)C FOWGHKUGYIXBQM-PNVBZASYSA-N 0.000 description 2
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 2
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical group C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 2
- 239000005977 Ethylene Substances 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical class NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical group [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- XUYPXLNMDZIRQH-LURJTMIESA-N N-acetyl-L-methionine Chemical class CSCC[C@@H](C(O)=O)NC(C)=O XUYPXLNMDZIRQH-LURJTMIESA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- WNLRTRBMVRJNCN-UHFFFAOYSA-L adipate(2-) Chemical compound [O-]C(=O)CCCCC([O-])=O WNLRTRBMVRJNCN-UHFFFAOYSA-L 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 125000005377 alkyl thioxy group Chemical group 0.000 description 2
- 125000005165 aryl thioxy group Chemical group 0.000 description 2
- 229940009098 aspartate Drugs 0.000 description 2
- 229940077388 benzenesulfonate Drugs 0.000 description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 2
- 125000004604 benzisothiazolyl group Chemical group S1N=C(C2=C1C=CC=C2)* 0.000 description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- XMIIGOLPHOKFCH-UHFFFAOYSA-N beta-phenylpropanoic acid Natural products OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 2
- 125000002618 bicyclic heterocycle group Chemical group 0.000 description 2
- IEPBPSSCIZTJIF-UHFFFAOYSA-N bis(2,2,2-trichloroethyl) carbonate Chemical compound ClC(Cl)(Cl)COC(=O)OCC(Cl)(Cl)Cl IEPBPSSCIZTJIF-UHFFFAOYSA-N 0.000 description 2
- JKJWYKGYGWOAHT-UHFFFAOYSA-N bis(prop-2-enyl) carbonate Chemical compound C=CCOC(=O)OCC=C JKJWYKGYGWOAHT-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 2
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 description 2
- 125000002837 carbocyclic group Chemical group 0.000 description 2
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical compound C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 description 2
- 150000001735 carboxylic acids Chemical class 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 2
- 229940043264 dodecyl sulfate Drugs 0.000 description 2
- 238000000799 fluorescence microscopy Methods 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical compound [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 125000004475 heteroaralkyl group Chemical group 0.000 description 2
- 125000005553 heteroaryloxy group Chemical group 0.000 description 2
- 125000005378 heteroarylthioxy group Chemical group 0.000 description 2
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 150000002466 imines Chemical class 0.000 description 2
- 125000001841 imino group Chemical group [H]N=* 0.000 description 2
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 2
- 125000001041 indolyl group Chemical group 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 125000002346 iodo group Chemical group I* 0.000 description 2
- 238000010884 ion-beam technique Methods 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 229940049920 malate Drugs 0.000 description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-L malate(2-) Chemical compound [O-]C(=O)C(O)CC([O-])=O BJEPYKJPYRNKOW-UHFFFAOYSA-L 0.000 description 2
- GPKUICFDWYEPTK-UHFFFAOYSA-N methoxycyclohexatriene Chemical compound COC1=CC=C=C[CH]1 GPKUICFDWYEPTK-UHFFFAOYSA-N 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 238000013188 needle biopsy Methods 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 102000039446 nucleic acids Human genes 0.000 description 2
- 108020004707 nucleic acids Proteins 0.000 description 2
- 150000007523 nucleic acids Chemical class 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 150000002894 organic compounds Chemical class 0.000 description 2
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 150000002989 phenols Chemical class 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 210000000557 podocyte Anatomy 0.000 description 2
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 238000010186 staining Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000000547 substituted alkyl group Chemical group 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 2
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 2
- 125000004434 sulfur atom Chemical group 0.000 description 2
- 150000003573 thiols Chemical class 0.000 description 2
- 125000000464 thioxo group Chemical group S=* 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- 125000004306 triazinyl group Chemical group 0.000 description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 210000002993 trophoblast Anatomy 0.000 description 2
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 2
- 238000012800 visualization Methods 0.000 description 2
- 229910052725 zinc Inorganic materials 0.000 description 2
- 239000011701 zinc Substances 0.000 description 2
- LSPHULWDVZXLIL-UHFFFAOYSA-N (+/-)-Camphoric acid Chemical compound CC1(C)C(C(O)=O)CCC1(C)C(O)=O LSPHULWDVZXLIL-UHFFFAOYSA-N 0.000 description 1
- DFNJPPOAVCXQQQ-UHFFFAOYSA-N (1,1,1-trichloro-2-methylpropan-2-yl) carbamate Chemical compound ClC(Cl)(Cl)C(C)(C)OC(N)=O DFNJPPOAVCXQQQ-UHFFFAOYSA-N 0.000 description 1
- AXTXAVIVKGDCLE-UHFFFAOYSA-N (1,1-dibromo-2-methylpropan-2-yl) carbamate Chemical compound BrC(Br)C(C)(C)OC(N)=O AXTXAVIVKGDCLE-UHFFFAOYSA-N 0.000 description 1
- AFCTUKSQTSHXEZ-UHFFFAOYSA-N (1-cyano-2-methylpropan-2-yl) carbamate Chemical compound N#CCC(C)(C)OC(N)=O AFCTUKSQTSHXEZ-UHFFFAOYSA-N 0.000 description 1
- FTVXFBJENACRRL-UHFFFAOYSA-N (1-hydroxypiperidin-2-yl) carbamate Chemical compound NC(=O)OC1CCCCN1O FTVXFBJENACRRL-UHFFFAOYSA-N 0.000 description 1
- KLWCNEYVHPBUNM-UHFFFAOYSA-N (1-methylcyclobutyl) carbamate Chemical compound NC(=O)OC1(C)CCC1 KLWCNEYVHPBUNM-UHFFFAOYSA-N 0.000 description 1
- AKIHTGIGOHBKGE-UHFFFAOYSA-N (1-methylcyclohexyl) carbamate Chemical compound NC(=O)OC1(C)CCCCC1 AKIHTGIGOHBKGE-UHFFFAOYSA-N 0.000 description 1
- ZLIHDHDAJVINAN-UHFFFAOYSA-N (2,4,6-trimethyl-3-pyridin-2-ylphenyl)methanimine Chemical compound CC1=C(C=N)C(C)=CC(C)=C1C1=CC=CC=N1 ZLIHDHDAJVINAN-UHFFFAOYSA-N 0.000 description 1
- KJOPTLWVYZCJBX-UHFFFAOYSA-N (2,4,6-trimethylphenyl)methyl carbamate Chemical compound CC1=CC(C)=C(COC(N)=O)C(C)=C1 KJOPTLWVYZCJBX-UHFFFAOYSA-N 0.000 description 1
- IUZVXNNZBSTDJT-UHFFFAOYSA-N (2,4,6-tritert-butylphenyl) carbamate Chemical compound CC(C)(C)C1=CC(C(C)(C)C)=C(OC(N)=O)C(C(C)(C)C)=C1 IUZVXNNZBSTDJT-UHFFFAOYSA-N 0.000 description 1
- LZZRHUUMSXNYBI-UHFFFAOYSA-N (2,4-dichlorophenyl)methyl carbamate Chemical compound NC(=O)OCC1=CC=C(Cl)C=C1Cl LZZRHUUMSXNYBI-UHFFFAOYSA-N 0.000 description 1
- LEDMDNAHWYVAPC-UHFFFAOYSA-N (2-carbamoylphenyl)methyl benzoate Chemical compound NC(=O)C1=CC=CC=C1COC(=O)C1=CC=CC=C1 LEDMDNAHWYVAPC-UHFFFAOYSA-N 0.000 description 1
- SWHAGWLVMRLFKO-UHFFFAOYSA-N (2-nitrophenyl)methyl carbamate Chemical compound NC(=O)OCC1=CC=CC=C1[N+]([O-])=O SWHAGWLVMRLFKO-UHFFFAOYSA-N 0.000 description 1
- PMIODTBPFKLUMF-UHFFFAOYSA-N (2-nitrophenyl)methyl hydrogen carbonate Chemical compound OC(=O)OCC1=CC=CC=C1[N+]([O-])=O PMIODTBPFKLUMF-UHFFFAOYSA-N 0.000 description 1
- ZTESKPLFUKCHOF-UHFFFAOYSA-N (3,4-dimethoxyphenyl)methyl hydrogen carbonate Chemical compound COC1=CC=C(COC(O)=O)C=C1OC ZTESKPLFUKCHOF-UHFFFAOYSA-N 0.000 description 1
- HIPYHINICCKLGX-UHFFFAOYSA-N (3,5-dimethoxyphenyl)methyl carbamate Chemical compound COC1=CC(COC(N)=O)=CC(OC)=C1 HIPYHINICCKLGX-UHFFFAOYSA-N 0.000 description 1
- YVOBGLMMNWZYCL-UHFFFAOYSA-N (3-nitrophenyl) carbamate Chemical compound NC(=O)OC1=CC=CC([N+]([O-])=O)=C1 YVOBGLMMNWZYCL-UHFFFAOYSA-N 0.000 description 1
- AWOKSNNHYRGYIA-UHFFFAOYSA-N (4,5-dimethoxy-2-nitrophenyl)methyl carbamate Chemical compound COC1=CC(COC(N)=O)=C([N+]([O-])=O)C=C1OC AWOKSNNHYRGYIA-UHFFFAOYSA-N 0.000 description 1
- XHTUZBFAOYRMHI-UHFFFAOYSA-N (4-bromophenyl)methyl carbamate Chemical compound NC(=O)OCC1=CC=C(Br)C=C1 XHTUZBFAOYRMHI-UHFFFAOYSA-N 0.000 description 1
- SODPIMGUZLOIPE-UHFFFAOYSA-N (4-chlorophenoxy)acetic acid Chemical compound OC(=O)COC1=CC=C(Cl)C=C1 SODPIMGUZLOIPE-UHFFFAOYSA-N 0.000 description 1
- HIIOEWGKFCWTJU-UHFFFAOYSA-N (4-chlorophenyl)methyl carbamate Chemical compound NC(=O)OCC1=CC=C(Cl)C=C1 HIIOEWGKFCWTJU-UHFFFAOYSA-N 0.000 description 1
- NULWVEYYQSYAHP-UHFFFAOYSA-N (4-cyanophenyl)methyl carbamate Chemical compound NC(=O)OCC1=CC=C(C#N)C=C1 NULWVEYYQSYAHP-UHFFFAOYSA-N 0.000 description 1
- IERCGNSLWQVTPC-UHFFFAOYSA-N (4-decoxyphenyl)methyl carbamate Chemical compound CCCCCCCCCCOC1=CC=C(COC(N)=O)C=C1 IERCGNSLWQVTPC-UHFFFAOYSA-N 0.000 description 1
- QXENIPSNYCZWNY-UHFFFAOYSA-N (4-methoxyphenyl)-diphenylmethanamine Chemical compound C1=CC(OC)=CC=C1C(N)(C=1C=CC=CC=1)C1=CC=CC=C1 QXENIPSNYCZWNY-UHFFFAOYSA-N 0.000 description 1
- OKLFHGKWEQKSDZ-UHFFFAOYSA-N (4-methoxyphenyl)methanimine Chemical compound COC1=CC=C(C=N)C=C1 OKLFHGKWEQKSDZ-UHFFFAOYSA-N 0.000 description 1
- SDEOSHAQCMPJIJ-UHFFFAOYSA-N (4-methoxyphenyl)methyl carbamate Chemical compound COC1=CC=C(COC(N)=O)C=C1 SDEOSHAQCMPJIJ-UHFFFAOYSA-N 0.000 description 1
- HZFLPRPFCHEBPQ-UHFFFAOYSA-N (4-methoxyphenyl)methyl hydrogen carbonate Chemical compound COC1=CC=C(COC(O)=O)C=C1 HZFLPRPFCHEBPQ-UHFFFAOYSA-N 0.000 description 1
- WNNZAHBBDIVWBB-UHFFFAOYSA-N (4-methylsulfanylphenyl) carbamate Chemical compound CSC1=CC=C(OC(N)=O)C=C1 WNNZAHBBDIVWBB-UHFFFAOYSA-N 0.000 description 1
- RZTAQRMRWPYVRR-UHFFFAOYSA-N (4-methylsulfinylphenyl)methyl carbamate Chemical compound CS(=O)C1=CC=C(COC(N)=O)C=C1 RZTAQRMRWPYVRR-UHFFFAOYSA-N 0.000 description 1
- LRJOVUGHUMSKFA-UHFFFAOYSA-N (4-nitrophenyl)methanimine Chemical compound [O-][N+](=O)C1=CC=C(C=N)C=C1 LRJOVUGHUMSKFA-UHFFFAOYSA-N 0.000 description 1
- HQNKOEZESXBYJA-UHFFFAOYSA-N (4-phenyldiazenylphenyl)methyl carbamate Chemical compound C1=CC(COC(=O)N)=CC=C1N=NC1=CC=CC=C1 HQNKOEZESXBYJA-UHFFFAOYSA-N 0.000 description 1
- 125000006583 (C1-C3) haloalkyl group Chemical group 0.000 description 1
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 description 1
- 125000006833 (C1-C5) alkylene group Chemical group 0.000 description 1
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 description 1
- 125000006648 (C1-C8) haloalkyl group Chemical group 0.000 description 1
- 125000006545 (C1-C9) alkyl group Chemical group 0.000 description 1
- 125000006592 (C2-C3) alkenyl group Chemical group 0.000 description 1
- 125000006593 (C2-C3) alkynyl group Chemical group 0.000 description 1
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 description 1
- 125000006713 (C5-C10) cycloalkyl group Chemical group 0.000 description 1
- 125000006569 (C5-C6) heterocyclic group Chemical group 0.000 description 1
- RASLWNGTMHFPIQ-AATRIKPKSA-N (e)-3-(2-nitrophenyl)prop-2-enamide Chemical compound NC(=O)\C=C\C1=CC=CC=C1[N+]([O-])=O RASLWNGTMHFPIQ-AATRIKPKSA-N 0.000 description 1
- ZOJKRWXDNYZASL-NSCUHMNNSA-N (e)-4-methoxybut-2-enoic acid Chemical compound COC\C=C\C(O)=O ZOJKRWXDNYZASL-NSCUHMNNSA-N 0.000 description 1
- GLUABPSZMHYCNO-UHFFFAOYSA-N 1,2,3,3a,4,5,6,6a-octahydropyrrolo[3,2-b]pyrrole Chemical compound N1CCC2NCCC21 GLUABPSZMHYCNO-UHFFFAOYSA-N 0.000 description 1
- 125000005904 1,2,3,4-tetrahydro-1,6-naphthyridinyl group Chemical group 0.000 description 1
- TTXKLVVJWALEOY-UHFFFAOYSA-N 1,2-benzoxazol-5-ylmethyl carbamate Chemical compound NC(=O)OCC1=CC=C2ON=CC2=C1 TTXKLVVJWALEOY-UHFFFAOYSA-N 0.000 description 1
- VAYTZRYEBVHVLE-UHFFFAOYSA-N 1,3-dioxol-2-one Chemical compound O=C1OC=CO1 VAYTZRYEBVHVLE-UHFFFAOYSA-N 0.000 description 1
- 125000005895 1,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl group Chemical group 0.000 description 1
- FJANNOJSTOGZHK-UHFFFAOYSA-N 1-adamantyl carbamate Chemical compound C1C(C2)CC3CC2CC1(OC(=O)N)C3 FJANNOJSTOGZHK-UHFFFAOYSA-N 0.000 description 1
- MNCMBBIFTVWHIP-UHFFFAOYSA-N 1-anthracen-9-yl-2,2,2-trifluoroethanone Chemical group C1=CC=C2C(C(=O)C(F)(F)F)=C(C=CC=C3)C3=CC2=C1 MNCMBBIFTVWHIP-UHFFFAOYSA-N 0.000 description 1
- XIUQHVQLGXTGGN-UHFFFAOYSA-N 1-cyclopropylethyl carbamate Chemical compound NC(=O)OC(C)C1CC1 XIUQHVQLGXTGGN-UHFFFAOYSA-N 0.000 description 1
- LNETULKMXZVUST-UHFFFAOYSA-N 1-naphthoic acid Chemical compound C1=CC=C2C(C(=O)O)=CC=CC2=C1 LNETULKMXZVUST-UHFFFAOYSA-N 0.000 description 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- 125000000530 1-propynyl group Chemical group [H]C([H])([H])C#C* 0.000 description 1
- 125000005894 1H-benzo[e][1,4]diazepinyl group Chemical group 0.000 description 1
- UPQQXPKAYZYUKO-UHFFFAOYSA-N 2,2,2-trichloroacetamide Chemical class OC(=N)C(Cl)(Cl)Cl UPQQXPKAYZYUKO-UHFFFAOYSA-N 0.000 description 1
- QPLJYAKLSCXZSF-UHFFFAOYSA-N 2,2,2-trichloroethyl carbamate Chemical compound NC(=O)OCC(Cl)(Cl)Cl QPLJYAKLSCXZSF-UHFFFAOYSA-N 0.000 description 1
- 125000000453 2,2,2-trichloroethyl group Chemical group [H]C([H])(*)C(Cl)(Cl)Cl 0.000 description 1
- NRKYWOKHZRQRJR-UHFFFAOYSA-N 2,2,2-trifluoroacetamide Chemical class NC(=O)C(F)(F)F NRKYWOKHZRQRJR-UHFFFAOYSA-N 0.000 description 1
- XNMOEWPBTNQAQB-UHFFFAOYSA-N 2,2,5,7,8-pentamethyl-3,4-dihydrochromene-6-sulfonamide Chemical compound C1CC(C)(C)OC2=C1C(C)=C(S(N)(=O)=O)C(C)=C2C XNMOEWPBTNQAQB-UHFFFAOYSA-N 0.000 description 1
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 1
- 125000005899 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl group Chemical group 0.000 description 1
- 125000005900 2,3-dihydrofuro[2,3-b]pyridinyl group Chemical group 0.000 description 1
- PXVUDLXXKGSXHH-UHFFFAOYSA-N 2,4,6-trimethoxybenzenesulfonamide Chemical compound COC1=CC(OC)=C(S(N)(=O)=O)C(OC)=C1 PXVUDLXXKGSXHH-UHFFFAOYSA-N 0.000 description 1
- YECJUZIGFPJWGQ-UHFFFAOYSA-N 2,4,6-trimethylbenzenesulfonamide Chemical compound CC1=CC(C)=C(S(N)(=O)=O)C(C)=C1 YECJUZIGFPJWGQ-UHFFFAOYSA-N 0.000 description 1
- FFFIRKXTFQCCKJ-UHFFFAOYSA-M 2,4,6-trimethylbenzoate Chemical compound CC1=CC(C)=C(C([O-])=O)C(C)=C1 FFFIRKXTFQCCKJ-UHFFFAOYSA-M 0.000 description 1
- 125000001917 2,4-dinitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C(=C1*)[N+]([O-])=O)[N+]([O-])=O 0.000 description 1
- YJRISODHEYGPEL-UHFFFAOYSA-N 2,6-dimethoxy-4-methylbenzenesulfonamide Chemical compound COC1=CC(C)=CC(OC)=C1S(N)(=O)=O YJRISODHEYGPEL-UHFFFAOYSA-N 0.000 description 1
- DWKLSWPFGOTZII-UHFFFAOYSA-N 2-(1-adamantyl)propan-2-yl carbamate Chemical compound C1C(C2)CC3CC2CC1(C(C)(OC(N)=O)C)C3 DWKLSWPFGOTZII-UHFFFAOYSA-N 0.000 description 1
- YURLCYGZYWDCHL-UHFFFAOYSA-N 2-(2,6-dichloro-4-methylphenoxy)acetic acid Chemical compound CC1=CC(Cl)=C(OCC(O)=O)C(Cl)=C1 YURLCYGZYWDCHL-UHFFFAOYSA-N 0.000 description 1
- DVCVYHFEWYAJCP-UHFFFAOYSA-N 2-(2-nitrophenoxy)acetamide Chemical compound NC(=O)COC1=CC=CC=C1[N+]([O-])=O DVCVYHFEWYAJCP-UHFFFAOYSA-N 0.000 description 1
- XHNQIEUUMIBVBX-UHFFFAOYSA-N 2-(3,5-dimethoxyphenyl)propan-2-yl carbamate Chemical compound COC1=CC(OC)=CC(C(C)(C)OC(N)=O)=C1 XHNQIEUUMIBVBX-UHFFFAOYSA-N 0.000 description 1
- KPJXVLVCTUUFBA-UHFFFAOYSA-N 2-(3,5-ditert-butylphenyl)propan-2-yl carbamate Chemical compound CC(C)(C)C1=CC(C(C)(C)C)=CC(C(C)(C)OC(N)=O)=C1 KPJXVLVCTUUFBA-UHFFFAOYSA-N 0.000 description 1
- JTQUNAJHSFYGSN-UHFFFAOYSA-N 2-(4-methylphenyl)sulfonylethyl carbamate Chemical compound CC1=CC=C(S(=O)(=O)CCOC(N)=O)C=C1 JTQUNAJHSFYGSN-UHFFFAOYSA-N 0.000 description 1
- RHTMIQNZSGHFCN-UHFFFAOYSA-N 2-(4-phenyldiazenylphenyl)propan-2-yl carbamate Chemical compound C1=CC(C(C)(OC(N)=O)C)=CC=C1N=NC1=CC=CC=C1 RHTMIQNZSGHFCN-UHFFFAOYSA-N 0.000 description 1
- KXKIBGGGFMXVBJ-UHFFFAOYSA-N 2-(4-phenylphenyl)propan-2-yl carbamate Chemical compound C1=CC(C(C)(OC(N)=O)C)=CC=C1C1=CC=CC=C1 KXKIBGGGFMXVBJ-UHFFFAOYSA-N 0.000 description 1
- FGJAPOYTPXTLPY-UHFFFAOYSA-N 2-(benzylideneamino)-4-chlorophenol Chemical compound OC1=CC=C(Cl)C=C1N=CC1=CC=CC=C1 FGJAPOYTPXTLPY-UHFFFAOYSA-N 0.000 description 1
- TYYAMZMDZWXHHA-UHFFFAOYSA-N 2-(dibromomethyl)benzoic acid Chemical compound OC(=O)C1=CC=CC=C1C(Br)Br TYYAMZMDZWXHHA-UHFFFAOYSA-N 0.000 description 1
- JGYNXZIYXGSEJH-UHFFFAOYSA-N 2-(methylsulfanylmethoxymethyl)benzoic acid Chemical compound CSCOCC1=CC=CC=C1C(O)=O JGYNXZIYXGSEJH-UHFFFAOYSA-N 0.000 description 1
- QXQMENSTZKYZCE-UHFFFAOYSA-N 2-[2,4-bis(2-methylbutan-2-yl)phenoxy]acetic acid Chemical compound CCC(C)(C)C1=CC=C(OCC(O)=O)C(C(C)(C)CC)=C1 QXQMENSTZKYZCE-UHFFFAOYSA-N 0.000 description 1
- XTRFZKJEMAVUIK-UHFFFAOYSA-N 2-[2,6-dichloro-4-(2,4,4-trimethylpentan-2-yl)phenoxy]acetic acid Chemical compound CC(C)(C)CC(C)(C)C1=CC(Cl)=C(OCC(O)=O)C(Cl)=C1 XTRFZKJEMAVUIK-UHFFFAOYSA-N 0.000 description 1
- UJRMHFPTLFNSTA-UHFFFAOYSA-N 2-chloro-2,2-diphenylacetic acid Chemical compound C=1C=CC=CC=1C(Cl)(C(=O)O)C1=CC=CC=C1 UJRMHFPTLFNSTA-UHFFFAOYSA-N 0.000 description 1
- SHHKMWMIKILKQW-UHFFFAOYSA-N 2-formylbenzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1C=O SHHKMWMIKILKQW-UHFFFAOYSA-N 0.000 description 1
- CJNZAXGUTKBIHP-UHFFFAOYSA-M 2-iodobenzoate Chemical compound [O-]C(=O)C1=CC=CC=C1I CJNZAXGUTKBIHP-UHFFFAOYSA-M 0.000 description 1
- UYCIUCIKUGYNBR-UHFFFAOYSA-N 2-iodoethyl carbamate Chemical compound NC(=O)OCCI UYCIUCIKUGYNBR-UHFFFAOYSA-N 0.000 description 1
- LPUAWADEOBHDIP-UHFFFAOYSA-N 2-methyl-2-(2-nitrophenoxy)propanamide Chemical compound NC(=O)C(C)(C)OC1=CC=CC=C1[N+]([O-])=O LPUAWADEOBHDIP-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-M 2-methylbenzenesulfonate Chemical compound CC1=CC=CC=C1S([O-])(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 1
- SDJNOBUNFYNROE-UHFFFAOYSA-N 2-methylbut-3-yn-2-yl carbamate Chemical compound C#CC(C)(C)OC(N)=O SDJNOBUNFYNROE-UHFFFAOYSA-N 0.000 description 1
- AUQKXXDHDKEBEY-UHFFFAOYSA-N 2-methylbutan-2-yl carbamate Chemical compound CCC(C)(C)OC(N)=O AUQKXXDHDKEBEY-UHFFFAOYSA-N 0.000 description 1
- BRUZQRBVNRKLJG-UHFFFAOYSA-N 2-methylpropyl carbamate Chemical compound CC(C)COC(N)=O BRUZQRBVNRKLJG-UHFFFAOYSA-N 0.000 description 1
- OWXVECVXBTWHPP-UHFFFAOYSA-N 2-methylsulfanylethyl carbamate Chemical compound CSCCOC(N)=O OWXVECVXBTWHPP-UHFFFAOYSA-N 0.000 description 1
- IXTODZAWAAKENF-UHFFFAOYSA-N 2-methylsulfonylethyl carbamate Chemical compound CS(=O)(=O)CCOC(N)=O IXTODZAWAAKENF-UHFFFAOYSA-N 0.000 description 1
- 229940080296 2-naphthalenesulfonate Drugs 0.000 description 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
- KLGQWSOYKYFBTR-UHFFFAOYSA-N 2-nitrobenzamide Chemical compound NC(=O)C1=CC=CC=C1[N+]([O-])=O KLGQWSOYKYFBTR-UHFFFAOYSA-N 0.000 description 1
- MUAUTBNKPSNTFM-UHFFFAOYSA-N 2-phenylethyl carbamate Chemical compound NC(=O)OCCC1=CC=CC=C1 MUAUTBNKPSNTFM-UHFFFAOYSA-N 0.000 description 1
- UCZSGRLQZLKLCQ-UHFFFAOYSA-N 2-phenylpropan-2-yl carbamate Chemical compound NC(=O)OC(C)(C)C1=CC=CC=C1 UCZSGRLQZLKLCQ-UHFFFAOYSA-N 0.000 description 1
- FCOXSVSQGYUZTB-UHFFFAOYSA-N 2-phosphanylethyl carbamate Chemical compound NC(=O)OCCP FCOXSVSQGYUZTB-UHFFFAOYSA-N 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- WYECGUSLBPACPT-UHFFFAOYSA-N 2-pyridin-4-ylpropan-2-yl carbamate Chemical compound NC(=O)OC(C)(C)C1=CC=NC=C1 WYECGUSLBPACPT-UHFFFAOYSA-N 0.000 description 1
- MZASHBBAFBWNFL-UHFFFAOYSA-N 2-trimethylsilylethanesulfonamide Chemical compound C[Si](C)(C)CCS(N)(=O)=O MZASHBBAFBWNFL-UHFFFAOYSA-N 0.000 description 1
- XSXPJNJLDYOPTF-UHFFFAOYSA-N 2-trimethylsilylethoxymethanamine Chemical compound C[Si](C)(C)CCOCN XSXPJNJLDYOPTF-UHFFFAOYSA-N 0.000 description 1
- QWYTUBPAXJYCTH-UHFFFAOYSA-N 2-trimethylsilylethyl carbamate Chemical compound C[Si](C)(C)CCOC(N)=O QWYTUBPAXJYCTH-UHFFFAOYSA-N 0.000 description 1
- GPVOTFQILZVCFP-UHFFFAOYSA-N 2-trityloxyacetic acid Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(OCC(=O)O)C1=CC=CC=C1 GPVOTFQILZVCFP-UHFFFAOYSA-N 0.000 description 1
- OEHZEBOCZWCVMK-UHFFFAOYSA-N 3-(4-hydroxyphenyl)propanamide Chemical compound NC(=O)CCC1=CC=C(O)C=C1 OEHZEBOCZWCVMK-UHFFFAOYSA-N 0.000 description 1
- NRZLJLXOGSCRAO-UHFFFAOYSA-N 3-(4-nitrophenyl)prop-2-enyl carbamate Chemical compound NC(=O)OCC=CC1=CC=C([N+]([O-])=O)C=C1 NRZLJLXOGSCRAO-UHFFFAOYSA-N 0.000 description 1
- MTZNODTZOSBYJW-UHFFFAOYSA-N 3-amino-5,5-dimethylcyclohex-2-en-1-one Chemical compound CC1(C)CC(N)=CC(=O)C1 MTZNODTZOSBYJW-UHFFFAOYSA-N 0.000 description 1
- SCLGGNBFBLJQFU-UHFFFAOYSA-N 3-aminopropyl acetate Chemical compound CC(=O)OCCCN SCLGGNBFBLJQFU-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- ZRPLANDPDWYOMZ-UHFFFAOYSA-N 3-cyclopentylpropionic acid Chemical compound OC(=O)CCC1CCCC1 ZRPLANDPDWYOMZ-UHFFFAOYSA-N 0.000 description 1
- UVODFYVXDPJZFJ-UHFFFAOYSA-N 3-methyl-3-nitrobutanamide Chemical compound [O-][N+](=O)C(C)(C)CC(N)=O UVODFYVXDPJZFJ-UHFFFAOYSA-N 0.000 description 1
- VYIBCOSBNVFEIW-UHFFFAOYSA-N 3-phenylpropanamide Chemical class NC(=O)CCC1=CC=CC=C1 VYIBCOSBNVFEIW-UHFFFAOYSA-N 0.000 description 1
- 125000005901 4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl group Chemical group 0.000 description 1
- 125000005902 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl group Chemical group 0.000 description 1
- 125000005903 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl group Chemical group 0.000 description 1
- UBARRNXCKBFUEN-UHFFFAOYSA-N 4,5-diphenyl-5h-1,3-oxazol-2-one Chemical compound N=1C(=O)OC(C=2C=CC=CC=2)C=1C1=CC=CC=C1 UBARRNXCKBFUEN-UHFFFAOYSA-N 0.000 description 1
- KJDSORYAHBAGPP-UHFFFAOYSA-N 4-(3,4-diaminophenyl)benzene-1,2-diamine;hydron;tetrachloride Chemical compound Cl.Cl.Cl.Cl.C1=C(N)C(N)=CC=C1C1=CC=C(N)C(N)=C1 KJDSORYAHBAGPP-UHFFFAOYSA-N 0.000 description 1
- NDRAHSMAGKWWFZ-UHFFFAOYSA-N 4-(methylsulfanylmethoxy)butanoic acid Chemical compound CSCOCCCC(O)=O NDRAHSMAGKWWFZ-UHFFFAOYSA-N 0.000 description 1
- BLEFBWAGWNSEGB-UHFFFAOYSA-N 4-[(4,8-dimethoxynaphthalen-1-yl)methyl]benzenesulfonamide Chemical compound C12=C(OC)C=CC=C2C(OC)=CC=C1CC1=CC=C(S(N)(=O)=O)C=C1 BLEFBWAGWNSEGB-UHFFFAOYSA-N 0.000 description 1
- WAGMYTXJRVPMGW-UHFFFAOYSA-N 4-azidobutanoic acid Chemical compound OC(=O)CCCN=[N+]=[N-] WAGMYTXJRVPMGW-UHFFFAOYSA-N 0.000 description 1
- QPSBONMVNZJUMM-UHFFFAOYSA-N 4-chloro-2-methanimidoylphenol Chemical compound OC1=CC=C(Cl)C=C1C=N QPSBONMVNZJUMM-UHFFFAOYSA-N 0.000 description 1
- XYOXIERJKILWCG-UHFFFAOYSA-N 4-chlorobutanamide Chemical compound NC(=O)CCCCl XYOXIERJKILWCG-UHFFFAOYSA-N 0.000 description 1
- UHAAUDAFKLCPEA-UHFFFAOYSA-N 4-methoxy-2,3,5,6-tetramethylbenzenesulfonamide Chemical compound COC1=C(C)C(C)=C(S(N)(=O)=O)C(C)=C1C UHAAUDAFKLCPEA-UHFFFAOYSA-N 0.000 description 1
- RVZNHBVRNJINRI-UHFFFAOYSA-N 4-methoxy-2,3,6-trimethylbenzenesulfonamide Chemical compound COC1=CC(C)=C(S(N)(=O)=O)C(C)=C1C RVZNHBVRNJINRI-UHFFFAOYSA-N 0.000 description 1
- ZJJLGMUSGUYZQP-UHFFFAOYSA-N 4-methoxy-2,6-dimethylbenzenesulfonamide Chemical compound COC1=CC(C)=C(S(N)(=O)=O)C(C)=C1 ZJJLGMUSGUYZQP-UHFFFAOYSA-N 0.000 description 1
- MSFQEZBRFPAFEX-UHFFFAOYSA-N 4-methoxybenzenesulfonamide Chemical compound COC1=CC=C(S(N)(=O)=O)C=C1 MSFQEZBRFPAFEX-UHFFFAOYSA-N 0.000 description 1
- KHKJLJHJTQRHSA-UHFFFAOYSA-N 4-methyl-4-nitropentanoic acid Chemical compound [O-][N+](=O)C(C)(C)CCC(O)=O KHKJLJHJTQRHSA-UHFFFAOYSA-N 0.000 description 1
- SPXOTSHWBDUUMT-UHFFFAOYSA-M 4-nitrobenzenesulfonate Chemical compound [O-][N+](=O)C1=CC=C(S([O-])(=O)=O)C=C1 SPXOTSHWBDUUMT-UHFFFAOYSA-M 0.000 description 1
- LUQVCHRDAGWYMG-UHFFFAOYSA-N 4-phenylbenzamide Chemical compound C1=CC(C(=O)N)=CC=C1C1=CC=CC=C1 LUQVCHRDAGWYMG-UHFFFAOYSA-N 0.000 description 1
- NNJMFJSKMRYHSR-UHFFFAOYSA-M 4-phenylbenzoate Chemical compound C1=CC(C(=O)[O-])=CC=C1C1=CC=CC=C1 NNJMFJSKMRYHSR-UHFFFAOYSA-M 0.000 description 1
- 125000005896 5,6-dihydro-4H-furo[3,2-b]pyrrolyl group Chemical group 0.000 description 1
- 125000005898 5,7-dihydro-4H-thieno[2,3-c]pyranyl group Chemical group 0.000 description 1
- 125000005897 6,7-dihydro-5H-furo[3,2-b]pyranyl group Chemical group 0.000 description 1
- GDXXYJRQFQZYNL-UHFFFAOYSA-N 9h-fluoren-1-ylmethyl carbamate Chemical compound C1C2=CC=CC=C2C2=C1C(COC(=O)N)=CC=C2 GDXXYJRQFQZYNL-UHFFFAOYSA-N 0.000 description 1
- 102100031260 Acyl-coenzyme A thioesterase THEM4 Human genes 0.000 description 1
- VVJKKWFAADXIJK-UHFFFAOYSA-N Allylamine Chemical compound NCC=C VVJKKWFAADXIJK-UHFFFAOYSA-N 0.000 description 1
- 229910017048 AsF6 Inorganic materials 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- KHBQMWCZKVMBLN-UHFFFAOYSA-N Benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1 KHBQMWCZKVMBLN-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- CPGQTYREPDBLCM-UHFFFAOYSA-N C.C=C(O)CN(CCN(CC(=O)O)C(C(=O)O)C(C)C)CC(=O)O.C=C(O)CN(CCN(CC(=O)O)C(C(=O)O)C(C)C)CC(=O)O.C=C(O)CN1CCN(CC(=O)O)CC(C(C)C)N(CC(=O)O)CC1.C=C(O)CN1CCN(CC(=O)O)CCN(C(C(=O)O)C(C)C)CC1.CC(=O)CN1CCN(CC(=O)O)CCN(C(C(=O)O)C(C)C)CCN(CC(=O)O)CC1.CC(=O)CN1CCN(CC(=O)O)CCN(CC(=O)O)C(C(C)C)CN(CC(=O)O)CC1 Chemical compound C.C=C(O)CN(CCN(CC(=O)O)C(C(=O)O)C(C)C)CC(=O)O.C=C(O)CN(CCN(CC(=O)O)C(C(=O)O)C(C)C)CC(=O)O.C=C(O)CN1CCN(CC(=O)O)CC(C(C)C)N(CC(=O)O)CC1.C=C(O)CN1CCN(CC(=O)O)CCN(C(C(=O)O)C(C)C)CC1.CC(=O)CN1CCN(CC(=O)O)CCN(C(C(=O)O)C(C)C)CCN(CC(=O)O)CC1.CC(=O)CN1CCN(CC(=O)O)CCN(CC(=O)O)C(C(C)C)CN(CC(=O)O)CC1 CPGQTYREPDBLCM-UHFFFAOYSA-N 0.000 description 1
- ZERNDLWYYKUTEY-QNIFPAIASA-N C.CCN1CCN(CC(=O)O)CCN(CC(=O)O)C(CC2=CC=C(CC(=O)/C=C/CC3=CC=C(O)C(O)=C3)C=C2)CN(CC(=O)O)CC1.CCN1CCN(CC(=O)O)CCN(CC(=O)O)C(CC2=CC=C(CC(=O)/C=C/CC3=CC=CC(O)=C3)C=C2)CN(CC(=O)O)CC1.CCN1CCN(CC(=O)O)CCN(CC(=O)O)C(CC2=CC=C(CC(=S)NCCC3=CC=C(O)C=C3)C=C2)CN(CC(=O)O)CC1 Chemical compound C.CCN1CCN(CC(=O)O)CCN(CC(=O)O)C(CC2=CC=C(CC(=O)/C=C/CC3=CC=C(O)C(O)=C3)C=C2)CN(CC(=O)O)CC1.CCN1CCN(CC(=O)O)CCN(CC(=O)O)C(CC2=CC=C(CC(=O)/C=C/CC3=CC=CC(O)=C3)C=C2)CN(CC(=O)O)CC1.CCN1CCN(CC(=O)O)CCN(CC(=O)O)C(CC2=CC=C(CC(=S)NCCC3=CC=C(O)C=C3)C=C2)CN(CC(=O)O)CC1 ZERNDLWYYKUTEY-QNIFPAIASA-N 0.000 description 1
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 description 1
- 125000004649 C2-C8 alkynyl group Chemical group 0.000 description 1
- HTMWZTQNGHHXCV-UHFFFAOYSA-N CC(=O)CN1CCN(CC(=O)O)CCN(CC(=O)O)C(C(C)C)CN(CC(=O)O)CC1 Chemical compound CC(=O)CN1CCN(CC(=O)O)CCN(CC(=O)O)C(C(C)C)CN(CC(=O)O)CC1 HTMWZTQNGHHXCV-UHFFFAOYSA-N 0.000 description 1
- KBPCCVWUMVGXGF-UHFFFAOYSA-N CC(C)CCCC(C)C Chemical compound CC(C)CCCC(C)C KBPCCVWUMVGXGF-UHFFFAOYSA-N 0.000 description 1
- SZWOFZPDSLAXBP-UHFFFAOYSA-N CC(C)CCNC(C)C Chemical compound CC(C)CCNC(C)C SZWOFZPDSLAXBP-UHFFFAOYSA-N 0.000 description 1
- LGAQJENWWYGFSN-UHFFFAOYSA-N CC=CC(C)C Chemical compound CC=CC(C)C LGAQJENWWYGFSN-UHFFFAOYSA-N 0.000 description 1
- UACKDQAJUTUZIT-KUPLNSMJSA-N CCN(CC)CC.NC1=CC=C(CC2CN(CC(=O)O)CCN(CC(=O)O)CCN(CC(=O)O)CCN2CC(=O)O)C=C1.O=C(/C=C/C1=CC(O)=C(O)C=C1)ON1C(=O)CCC1=O.O=C(O)/C=C/C1=CC(O)=C(O)C=C1.O=C=O.O=C=O.[2H]CF.[H]CN1CCN(CC(=O)O)CCN(CC(=O)O)CC(C2=CC=C(NC(=O)/C=C/C3=CC(O)=C(O)C=C3)C=C2)N(C[H])CC1 Chemical compound CCN(CC)CC.NC1=CC=C(CC2CN(CC(=O)O)CCN(CC(=O)O)CCN(CC(=O)O)CCN2CC(=O)O)C=C1.O=C(/C=C/C1=CC(O)=C(O)C=C1)ON1C(=O)CCC1=O.O=C(O)/C=C/C1=CC(O)=C(O)C=C1.O=C=O.O=C=O.[2H]CF.[H]CN1CCN(CC(=O)O)CCN(CC(=O)O)CC(C2=CC=C(NC(=O)/C=C/C3=CC(O)=C(O)C=C3)C=C2)N(C[H])CC1 UACKDQAJUTUZIT-KUPLNSMJSA-N 0.000 description 1
- KOHWILDAPXQSTO-AXXUKJGBSA-N CCN(CC)CC.NC1=CC=C(CC2CN(CC(=O)O)CCN(CC(=O)O)CCN(CC(=O)O)CCN2CC(=O)O)C=C1.O=C(/C=C/C1=CC(O)=C(O)C=C1)ON1C(=O)CCC1=O.O=C(O)/C=C/C1=CC(O)=C(O)C=C1.O=C=O.O=C=O.[2H]CF.[H]CN1CCN(CC(=O)O)CCN(CC(=O)O)CC(C2=CC=C(NC(=O)/C=C/C3=CC=C(O)C=C3)C=C2)N(C[H])CC1 Chemical compound CCN(CC)CC.NC1=CC=C(CC2CN(CC(=O)O)CCN(CC(=O)O)CCN(CC(=O)O)CCN2CC(=O)O)C=C1.O=C(/C=C/C1=CC(O)=C(O)C=C1)ON1C(=O)CCC1=O.O=C(O)/C=C/C1=CC(O)=C(O)C=C1.O=C=O.O=C=O.[2H]CF.[H]CN1CCN(CC(=O)O)CCN(CC(=O)O)CC(C2=CC=C(NC(=O)/C=C/C3=CC=C(O)C=C3)C=C2)N(C[H])CC1 KOHWILDAPXQSTO-AXXUKJGBSA-N 0.000 description 1
- HRQDACXZPLJECY-TTZHHZLVSA-N CCN(CC)CC.NCCC1=CC=C(O)C=C1.O=C(O)CN1CCN(CC(=O)O)CCN(CC(=O)O)C(CC2=CC=C(N=C=S)C=C2)CN(CC(=O)O)CC1.O=C=O.O=C=O.O=C=O.[2H]CF.[H]CN1CCN(CC(=O)O)CCN(C[H])CC(C2=CC=C(NC(=S)NCCC3=CC=C(O)C=C3)C=C2)N(C[H])CC1 Chemical compound CCN(CC)CC.NCCC1=CC=C(O)C=C1.O=C(O)CN1CCN(CC(=O)O)CCN(CC(=O)O)C(CC2=CC=C(N=C=S)C=C2)CN(CC(=O)O)CC1.O=C=O.O=C=O.O=C=O.[2H]CF.[H]CN1CCN(CC(=O)O)CCN(C[H])CC(C2=CC=C(NC(=S)NCCC3=CC=C(O)C=C3)C=C2)N(C[H])CC1 HRQDACXZPLJECY-TTZHHZLVSA-N 0.000 description 1
- WBNVHQOQTXUNIO-SGLXJCBISA-N CCN1CCN(CC(=O)O)CCN(CC(=O)O)C(CC2=CC=C(NC(=O)/C=C/C3=CC(O)=C(O)C=C3)C=C2)CN(CC(=O)O)CC1.CCN1CCN(CC(=O)O)CCN(CC(=O)O)C(CC2=CC=C(NC(=O)CCC3=CC=C(O)C=C3)C=C2)CN(CC(=O)O)CC1.CCN1CCN(CC(=O)O)CCN(CC(=O)O)C(CC2=CC=C(NC(=S)NCCC3=CC=C(O)C=C3)C=C2)CN(CC(=O)O)CC1 Chemical compound CCN1CCN(CC(=O)O)CCN(CC(=O)O)C(CC2=CC=C(NC(=O)/C=C/C3=CC(O)=C(O)C=C3)C=C2)CN(CC(=O)O)CC1.CCN1CCN(CC(=O)O)CCN(CC(=O)O)C(CC2=CC=C(NC(=O)CCC3=CC=C(O)C=C3)C=C2)CN(CC(=O)O)CC1.CCN1CCN(CC(=O)O)CCN(CC(=O)O)C(CC2=CC=C(NC(=S)NCCC3=CC=C(O)C=C3)C=C2)CN(CC(=O)O)CC1 WBNVHQOQTXUNIO-SGLXJCBISA-N 0.000 description 1
- QTNQXGZRJWKWGX-UHFFFAOYSA-N CCN1CCN(CC(=O)O)CCN(CC)CC(CC(C)C)N(CC)CC1.ClC(Cl)Cl.O=C=O.O=C=O.[CH+3].[H]CN1CCN(CC(=O)O)CCN(CC(=O)O)CC(CC(C)C)N(C[H])CC1 Chemical compound CCN1CCN(CC(=O)O)CCN(CC)CC(CC(C)C)N(CC)CC1.ClC(Cl)Cl.O=C=O.O=C=O.[CH+3].[H]CN1CCN(CC(=O)O)CCN(CC(=O)O)CC(CC(C)C)N(C[H])CC1 QTNQXGZRJWKWGX-UHFFFAOYSA-N 0.000 description 1
- ALDPPQDMEDTAAB-ZEIPCWFSSA-A CCN1CCN(CC(=O)[O-])CCN(CC(=O)[O-])C(CC2=CC=C(NC(=O)/C=C/C3=CC(O)=C(O)C=C3)C=C2)CN(CC(=O)[O-])CC1.CCN1CCN(CC(=O)[O-])CCN(CC(=O)[O-])C(CC2=CC=C(NC(=O)/C=C/C3=CC(O)=C(O)C=C3)C=C2)CN(CC(=O)[O-])CC1.CCN1CCN(CC(=O)[O-])CCN(CC(=O)[O-])C(CC2=CC=C(NC(=O)CCC3=CC=C(O)C=C3)C=C2)CN(CC(=O)[O-])CC1.CCN1CCN(CC(=O)[O-])CCN(CC(=O)[O-])C(CC2=CC=C(NC(=O)CCC3=CC=C(O)C=C3)C=C2)CN(CC(=O)[O-])CC1.CCN1CCN(CC(=O)[O-])CCN(CC(=O)[O-])C(CC2=CC=C(NC(=S)NCCC3=CC=C(O)C=C3)C=C2)CN(CC(=O)[O-])CC1.CCN1CCN(CC(=O)[O-])CCN(CC(=O)[O-])C(CC2=CC=C(NC(=S)NCCC3=CC=C(O)C=C3)C=C2)CN(CC(=O)[O-])CC1.[Pr+3].[Pr+3].[Pr+3].[Y+3].[Y+3].[Y+3] Chemical compound CCN1CCN(CC(=O)[O-])CCN(CC(=O)[O-])C(CC2=CC=C(NC(=O)/C=C/C3=CC(O)=C(O)C=C3)C=C2)CN(CC(=O)[O-])CC1.CCN1CCN(CC(=O)[O-])CCN(CC(=O)[O-])C(CC2=CC=C(NC(=O)/C=C/C3=CC(O)=C(O)C=C3)C=C2)CN(CC(=O)[O-])CC1.CCN1CCN(CC(=O)[O-])CCN(CC(=O)[O-])C(CC2=CC=C(NC(=O)CCC3=CC=C(O)C=C3)C=C2)CN(CC(=O)[O-])CC1.CCN1CCN(CC(=O)[O-])CCN(CC(=O)[O-])C(CC2=CC=C(NC(=O)CCC3=CC=C(O)C=C3)C=C2)CN(CC(=O)[O-])CC1.CCN1CCN(CC(=O)[O-])CCN(CC(=O)[O-])C(CC2=CC=C(NC(=S)NCCC3=CC=C(O)C=C3)C=C2)CN(CC(=O)[O-])CC1.CCN1CCN(CC(=O)[O-])CCN(CC(=O)[O-])C(CC2=CC=C(NC(=S)NCCC3=CC=C(O)C=C3)C=C2)CN(CC(=O)[O-])CC1.[Pr+3].[Pr+3].[Pr+3].[Y+3].[Y+3].[Y+3] ALDPPQDMEDTAAB-ZEIPCWFSSA-A 0.000 description 1
- PPLJDXUNKRIEML-RTLGDECASA-A CCN1CCN(CC(=O)[O-])CCN(CC(=O)[O-])C(CC2=CC=C(NC(=O)/C=C/C3=CC(O)=C(O)C=C3)C=C2)CN(CC(=O)[O-])CC1.CCN1CCN(CC(=O)[O-])CCN(CC(=O)[O-])C(CC2=CC=C(NC(=O)/C=C/C3=CC(O)=C(O)C=C3)C=C2)CN(CC(=O)[O-])CC1.CCN1CCN(CC(=O)[O-])CCN(CC(=O)[O-])C(CC2=CC=C(NC(=O)CCC3=CC=C(O)C=C3)C=C2)CN(CC(=O)[O-])CC1.CCN1CCN(CC(=O)[O-])CCN(CC(=O)[O-])C(CC2=CC=C(NC(=S)NCCC3=CC=C(O)C=C3)C=C2)CN(CC(=O)[O-])CC1.CCN1CCN(CC(=O)[O-])CCN(CC(=O)[O-])C(CC2=CC=C(NC(=S)NCCC3=CC=C(O)C=C3)C=C2)CN(CC(=O)[O-])CC1.[Pr+3].[Pr+3].[Y+3].[Y+3].[Y+3] Chemical compound CCN1CCN(CC(=O)[O-])CCN(CC(=O)[O-])C(CC2=CC=C(NC(=O)/C=C/C3=CC(O)=C(O)C=C3)C=C2)CN(CC(=O)[O-])CC1.CCN1CCN(CC(=O)[O-])CCN(CC(=O)[O-])C(CC2=CC=C(NC(=O)/C=C/C3=CC(O)=C(O)C=C3)C=C2)CN(CC(=O)[O-])CC1.CCN1CCN(CC(=O)[O-])CCN(CC(=O)[O-])C(CC2=CC=C(NC(=O)CCC3=CC=C(O)C=C3)C=C2)CN(CC(=O)[O-])CC1.CCN1CCN(CC(=O)[O-])CCN(CC(=O)[O-])C(CC2=CC=C(NC(=S)NCCC3=CC=C(O)C=C3)C=C2)CN(CC(=O)[O-])CC1.CCN1CCN(CC(=O)[O-])CCN(CC(=O)[O-])C(CC2=CC=C(NC(=S)NCCC3=CC=C(O)C=C3)C=C2)CN(CC(=O)[O-])CC1.[Pr+3].[Pr+3].[Y+3].[Y+3].[Y+3] PPLJDXUNKRIEML-RTLGDECASA-A 0.000 description 1
- YRHBVBHSFHULRH-UHFFFAOYSA-K CCN1CCN(CC(=O)[O-])CCN(CC(=O)[O-])C(CC2=CC=C(NC(=O)CCC3=CC=C(O)C=C3)C=C2)CN(CC(=O)[O-])CC1.[Pr+3] Chemical compound CCN1CCN(CC(=O)[O-])CCN(CC(=O)[O-])C(CC2=CC=C(NC(=O)CCC3=CC=C(O)C=C3)C=C2)CN(CC(=O)[O-])CC1.[Pr+3] YRHBVBHSFHULRH-UHFFFAOYSA-K 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical group NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical group [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- RBNPOMFGQQGHHO-UWTATZPHSA-M D-glycerate Chemical compound OC[C@@H](O)C([O-])=O RBNPOMFGQQGHHO-UWTATZPHSA-M 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- AEMRFAOFKBGASW-UHFFFAOYSA-M Glycolate Chemical compound OCC([O-])=O AEMRFAOFKBGASW-UHFFFAOYSA-M 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000638510 Homo sapiens Acyl-coenzyme A thioesterase THEM4 Proteins 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 102000012411 Intermediate Filament Proteins Human genes 0.000 description 1
- 108010061998 Intermediate Filament Proteins Proteins 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 238000006751 Mitsunobu reaction Methods 0.000 description 1
- 101100005297 Mus musculus Cat gene Proteins 0.000 description 1
- LKJPYSCBVHEWIU-UHFFFAOYSA-N N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methylpropanamide Chemical compound C=1C=C(C#N)C(C(F)(F)F)=CC=1NC(=O)C(O)(C)CS(=O)(=O)C1=CC=C(F)C=C1 LKJPYSCBVHEWIU-UHFFFAOYSA-N 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical class NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 1
- CXMZZWCGCQVYRT-UHFFFAOYSA-N O=C(O)CN1CCN(CC(=O)O)CCN(CC(=O)O)C(CC2=CC=C(NC(=O)CCC3=CC=C(O)C=C3)C=C2)CN(CC(=O)O)CC1 Chemical compound O=C(O)CN1CCN(CC(=O)O)CCN(CC(=O)O)C(CC2=CC=C(NC(=O)CCC3=CC=C(O)C=C3)C=C2)CN(CC(=O)O)CC1 CXMZZWCGCQVYRT-UHFFFAOYSA-N 0.000 description 1
- OVDZATIXVJZJKH-UHFFFAOYSA-N O=C(O)CN1CCN(CC(=O)O)CCN(CC(=O)O)C(CC2=CC=C(NC(=S)NCCC3=CC=C(O)C=C3)C=C2)CN(CC(=O)O)CC1 Chemical compound O=C(O)CN1CCN(CC(=O)O)CCN(CC(=O)O)C(CC2=CC=C(NC(=S)NCCC3=CC=C(O)C=C3)C=C2)CN(CC(=O)O)CC1 OVDZATIXVJZJKH-UHFFFAOYSA-N 0.000 description 1
- WOWHUSIRGQDXMO-BJMVGYQFSA-N O=C(O)CN1CCN(CC(=O)O)CCN(CC(=O)O)C(CCC2=CC=C(NC(=O)/C=C/C3=CC(O)=C(O)C=C3)C=C2)CN(CC(=O)O)CC1 Chemical compound O=C(O)CN1CCN(CC(=O)O)CCN(CC(=O)O)C(CCC2=CC=C(NC(=O)/C=C/C3=CC(O)=C(O)C=C3)C=C2)CN(CC(=O)O)CC1 WOWHUSIRGQDXMO-BJMVGYQFSA-N 0.000 description 1
- MSYGZCNKYWRPCB-ZFXMFRGYSA-K O=C([O-])CN1CCN(CC(=O)O)CCN(CC(=O)[O-])CC(CC2=CC=C(NC(=O)/C=C/C3=CC(O)=C(O)C=C3)C=C2)N(CC(=O)[O-])CC1.[Pr+3] Chemical compound O=C([O-])CN1CCN(CC(=O)O)CCN(CC(=O)[O-])CC(CC2=CC=C(NC(=O)/C=C/C3=CC(O)=C(O)C=C3)C=C2)N(CC(=O)[O-])CC1.[Pr+3] MSYGZCNKYWRPCB-ZFXMFRGYSA-K 0.000 description 1
- YFYWPMNXDKNLGJ-ZFXMFRGYSA-K O=C([O-])CN1CCN(CC(=O)O)CCN(CC(=O)[O-])CC(CC2=CC=C(NC(=O)/C=C/C3=CC(O)=C(O)C=C3)C=C2)N(CC(=O)[O-])CC1.[Y+3] Chemical compound O=C([O-])CN1CCN(CC(=O)O)CCN(CC(=O)[O-])CC(CC2=CC=C(NC(=O)/C=C/C3=CC(O)=C(O)C=C3)C=C2)N(CC(=O)[O-])CC1.[Y+3] YFYWPMNXDKNLGJ-ZFXMFRGYSA-K 0.000 description 1
- VYZDANQRSYRGSU-UHFFFAOYSA-K O=C([O-])CN1CCN(CC(=O)O)CCN(CC(=O)[O-])CC(CC2=CC=C(NC(=O)CCC3=CC=C(O)C=C3)C=C2)N(CC(=O)[O-])CC1.[Pr+3] Chemical compound O=C([O-])CN1CCN(CC(=O)O)CCN(CC(=O)[O-])CC(CC2=CC=C(NC(=O)CCC3=CC=C(O)C=C3)C=C2)N(CC(=O)[O-])CC1.[Pr+3] VYZDANQRSYRGSU-UHFFFAOYSA-K 0.000 description 1
- BOOZPAMCBXDVFZ-UHFFFAOYSA-K O=C([O-])CN1CCN(CC(=O)O)CCN(CC(=O)[O-])CC(CC2=CC=C(NC(=O)CCC3=CC=C(O)C=C3)C=C2)N(CC(=O)[O-])CC1.[Y+3] Chemical compound O=C([O-])CN1CCN(CC(=O)O)CCN(CC(=O)[O-])CC(CC2=CC=C(NC(=O)CCC3=CC=C(O)C=C3)C=C2)N(CC(=O)[O-])CC1.[Y+3] BOOZPAMCBXDVFZ-UHFFFAOYSA-K 0.000 description 1
- WDKFDZWYCMAAJN-UHFFFAOYSA-K O=C([O-])CN1CCN(CC(=O)O)CCN(CC(=O)[O-])CC(CC2=CC=C(NC(=S)NCCCC3=CC=C(O)C=C3)C=C2)N(CC(=O)[O-])CC1.[Pr+3] Chemical compound O=C([O-])CN1CCN(CC(=O)O)CCN(CC(=O)[O-])CC(CC2=CC=C(NC(=S)NCCCC3=CC=C(O)C=C3)C=C2)N(CC(=O)[O-])CC1.[Pr+3] WDKFDZWYCMAAJN-UHFFFAOYSA-K 0.000 description 1
- YCUXCHGWXUUNNR-UHFFFAOYSA-K O=C([O-])CN1CCN(CC(=O)O)CCN(CC(=O)[O-])CC(CC2=CC=C(NC(=S)NCCCC3=CC=C(O)C=C3)C=C2)N(CC(=O)[O-])CC1.[Y+3] Chemical compound O=C([O-])CN1CCN(CC(=O)O)CCN(CC(=O)[O-])CC(CC2=CC=C(NC(=S)NCCCC3=CC=C(O)C=C3)C=C2)N(CC(=O)[O-])CC1.[Y+3] YCUXCHGWXUUNNR-UHFFFAOYSA-K 0.000 description 1
- 108700020962 Peroxidase Proteins 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- 229910006074 SO2NH2 Inorganic materials 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M Thiocyanate anion Chemical compound [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- CLPYVPMXLNNKLB-UHFFFAOYSA-N [(2-nitrophenyl)-phenylmethyl] carbamate Chemical compound C=1C=CC=C([N+]([O-])=O)C=1C(OC(=O)N)C1=CC=CC=C1 CLPYVPMXLNNKLB-UHFFFAOYSA-N 0.000 description 1
- LXKLUWFIBVXFGX-QPJJXVBHSA-N [(e)-3-phenylprop-2-enyl] carbamate Chemical compound NC(=O)OC\C=C\C1=CC=CC=C1 LXKLUWFIBVXFGX-QPJJXVBHSA-N 0.000 description 1
- MQLDYIKXBMSDCL-UHFFFAOYSA-N [2,4-bis(methylsulfanyl)phenyl] carbamate Chemical compound CSC1=CC=C(OC(N)=O)C(SC)=C1 MQLDYIKXBMSDCL-UHFFFAOYSA-N 0.000 description 1
- OJUHIDQVEFLXSE-UHFFFAOYSA-N [2-(4-methoxyphenyl)-2-oxoethyl] carbamate Chemical compound COC1=CC=C(C(=O)COC(N)=O)C=C1 OJUHIDQVEFLXSE-UHFFFAOYSA-N 0.000 description 1
- XSXGGUVGOHDUPF-UHFFFAOYSA-N [4-(carbamoyloxymethyl)phenyl]boronic acid Chemical compound NC(=O)OCC1=CC=C(B(O)O)C=C1 XSXGGUVGOHDUPF-UHFFFAOYSA-N 0.000 description 1
- 229940022663 acetate Drugs 0.000 description 1
- GCPWJFKTWGFEHH-UHFFFAOYSA-N acetoacetamide Chemical compound CC(=O)CC(N)=O GCPWJFKTWGFEHH-UHFFFAOYSA-N 0.000 description 1
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 description 1
- 125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 150000001266 acyl halides Chemical class 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 125000005585 adamantoate group Chemical group 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 125000005194 alkoxycarbonyloxy group Chemical group 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 125000002877 alkyl aryl group Chemical group 0.000 description 1
- 150000008055 alkyl aryl sulfonates Chemical class 0.000 description 1
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 description 1
- 150000008052 alkyl sulfonates Chemical class 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 150000001413 amino acids Chemical group 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- DQEFBVRIBYYPLE-UHFFFAOYSA-N anthracen-9-ylmethyl carbamate Chemical compound C1=CC=C2C(COC(=O)N)=C(C=CC=C3)C3=CC2=C1 DQEFBVRIBYYPLE-UHFFFAOYSA-N 0.000 description 1
- FKFZOFZWJNHJDE-UHFFFAOYSA-N anthracene-9-sulfonamide Chemical compound C1=CC=C2C(S(=O)(=O)N)=C(C=CC=C3)C3=CC2=C1 FKFZOFZWJNHJDE-UHFFFAOYSA-N 0.000 description 1
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
- 125000001769 aryl amino group Chemical group 0.000 description 1
- 125000005199 aryl carbonyloxy group Chemical group 0.000 description 1
- 125000005200 aryloxy carbonyloxy group Chemical group 0.000 description 1
- 229940072107 ascorbate Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229940067597 azelate Drugs 0.000 description 1
- 125000003725 azepanyl group Chemical group 0.000 description 1
- 125000002785 azepinyl group Chemical group 0.000 description 1
- 125000002393 azetidinyl group Chemical group 0.000 description 1
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 description 1
- DUXANUSOCMOJSI-UHFFFAOYSA-N benzhydryl carbamate Chemical compound C=1C=CC=CC=1C(OC(=O)N)C1=CC=CC=C1 DUXANUSOCMOJSI-UHFFFAOYSA-N 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000004603 benzisoxazolyl group Chemical group O1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 229940050390 benzoate Drugs 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- KVPFKMBYCSISTN-UHFFFAOYSA-N benzylsulfanylformic acid Chemical compound OC(=O)SCC1=CC=CC=C1 KVPFKMBYCSISTN-UHFFFAOYSA-N 0.000 description 1
- BVCRERJDOOBZOH-UHFFFAOYSA-N bicyclo[2.2.1]heptanyl Chemical group C1C[C+]2CC[C-]1C2 BVCRERJDOOBZOH-UHFFFAOYSA-N 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- 238000001574 biopsy Methods 0.000 description 1
- 229960002685 biotin Drugs 0.000 description 1
- 235000020958 biotin Nutrition 0.000 description 1
- 239000011616 biotin Substances 0.000 description 1
- UXXXZMDJQLPQPH-UHFFFAOYSA-N bis(2-methylpropyl) carbonate Chemical compound CC(C)COC(=O)OCC(C)C UXXXZMDJQLPQPH-UHFFFAOYSA-N 0.000 description 1
- HROGQYMZWGPHIB-UHFFFAOYSA-N bis(4-methoxyphenyl)methanamine Chemical compound C1=CC(OC)=CC=C1C(N)C1=CC=C(OC)C=C1 HROGQYMZWGPHIB-UHFFFAOYSA-N 0.000 description 1
- ACBQROXDOHKANW-UHFFFAOYSA-N bis(4-nitrophenyl) carbonate Chemical compound C1=CC([N+](=O)[O-])=CC=C1OC(=O)OC1=CC=C([N+]([O-])=O)C=C1 ACBQROXDOHKANW-UHFFFAOYSA-N 0.000 description 1
- JZUVESQYEHERMD-UHFFFAOYSA-N bis[(4-nitrophenyl)methyl] carbonate Chemical compound C1=CC([N+](=O)[O-])=CC=C1COC(=O)OCC1=CC=C([N+]([O-])=O)C=C1 JZUVESQYEHERMD-UHFFFAOYSA-N 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 125000003865 brosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Br)S(*)(=O)=O 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- FATUQANACHZLRT-KMRXSBRUSA-L calcium glucoheptonate Chemical compound [Ca+2].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)C([O-])=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)C([O-])=O FATUQANACHZLRT-KMRXSBRUSA-L 0.000 description 1
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 1
- 235000013877 carbamide Nutrition 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 230000009920 chelation Effects 0.000 description 1
- 229910052729 chemical element Inorganic materials 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229910001914 chlorine tetroxide Inorganic materials 0.000 description 1
- VXIVSQZSERGHQP-UHFFFAOYSA-N chloroacetamide Chemical class NC(=O)CCl VXIVSQZSERGHQP-UHFFFAOYSA-N 0.000 description 1
- FOCAUTSVDIKZOP-UHFFFAOYSA-M chloroacetate Chemical compound [O-]C(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-M 0.000 description 1
- 229940089960 chloroacetate Drugs 0.000 description 1
- 125000003016 chromanyl group Chemical group O1C(CCC2=CC=CC=C12)* 0.000 description 1
- 125000004230 chromenyl group Chemical group O1C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- LDHQCZJRKDOVOX-NSCUHMNNSA-M crotonate Chemical compound C\C=C\C([O-])=O LDHQCZJRKDOVOX-NSCUHMNNSA-M 0.000 description 1
- 125000001047 cyclobutenyl group Chemical group C1(=CCC1)* 0.000 description 1
- LWABFMLTBBNLTA-UHFFFAOYSA-N cyclobutyl carbamate Chemical compound NC(=O)OC1CCC1 LWABFMLTBBNLTA-UHFFFAOYSA-N 0.000 description 1
- 125000002188 cycloheptatrienyl group Chemical group C1(=CC=CC=CC1)* 0.000 description 1
- 125000001162 cycloheptenyl group Chemical group C1(=CCCCCC1)* 0.000 description 1
- 125000003678 cyclohexadienyl group Chemical group C1(=CC=CCC1)* 0.000 description 1
- NNGAQKAUYDTUQR-UHFFFAOYSA-N cyclohexanimine Chemical compound N=C1CCCCC1 NNGAQKAUYDTUQR-UHFFFAOYSA-N 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- AUELWJRRASQDKI-UHFFFAOYSA-N cyclohexyl carbamate Chemical compound NC(=O)OC1CCCCC1 AUELWJRRASQDKI-UHFFFAOYSA-N 0.000 description 1
- 125000004090 cyclononenyl group Chemical group C1(=CCCCCCCC1)* 0.000 description 1
- 125000006547 cyclononyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000000522 cyclooctenyl group Chemical group C1(=CCCCCCC1)* 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- JMFVWNKPLURQMI-UHFFFAOYSA-N cyclopentyl carbamate Chemical compound NC(=O)OC1CCCC1 JMFVWNKPLURQMI-UHFFFAOYSA-N 0.000 description 1
- 125000000298 cyclopropenyl group Chemical group [H]C1=C([H])C1([H])* 0.000 description 1
- UWYRVVJXSNXVAI-UHFFFAOYSA-N cyclopropylmethyl carbamate Chemical compound NC(=O)OCC1CC1 UWYRVVJXSNXVAI-UHFFFAOYSA-N 0.000 description 1
- 230000002380 cytological effect Effects 0.000 description 1
- 125000001295 dansyl group Chemical group [H]C1=C([H])C(N(C([H])([H])[H])C([H])([H])[H])=C2C([H])=C([H])C([H])=C(C2=C1[H])S(*)(=O)=O 0.000 description 1
- 125000005892 decahydro-1,8-naphthyridinyl group Chemical group 0.000 description 1
- 125000004652 decahydroisoquinolinyl group Chemical group C1(NCCC2CCCCC12)* 0.000 description 1
- 125000005508 decahydronaphthalenyl group Chemical group 0.000 description 1
- 125000005891 decahydronaphthyridinyl group Chemical group 0.000 description 1
- 125000004856 decahydroquinolinyl group Chemical group N1(CCCC2CCCCC12)* 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 239000012954 diazonium Substances 0.000 description 1
- 150000001989 diazonium salts Chemical class 0.000 description 1
- PIZLBWGMERQCOC-UHFFFAOYSA-N dibenzyl carbonate Chemical compound C=1C=CC=CC=1COC(=O)OCC1=CC=CC=C1 PIZLBWGMERQCOC-UHFFFAOYSA-N 0.000 description 1
- 229940120124 dichloroacetate Drugs 0.000 description 1
- JXTHNDFMNIQAHM-UHFFFAOYSA-N dichloroacetic acid Chemical compound OC(=O)C(Cl)Cl JXTHNDFMNIQAHM-UHFFFAOYSA-N 0.000 description 1
- 150000004683 dihydrates Chemical class 0.000 description 1
- 125000000723 dihydrobenzofuranyl group Chemical group O1C(CC2=C1C=CC=C2)* 0.000 description 1
- 125000004582 dihydrobenzothienyl group Chemical group S1C(CC2=C1C=CC=C2)* 0.000 description 1
- 125000004852 dihydrofuranyl group Chemical group O1C(CC=C1)* 0.000 description 1
- 125000004655 dihydropyridinyl group Chemical group N1(CC=CC=C1)* 0.000 description 1
- 125000005054 dihydropyrrolyl group Chemical group [H]C1=C([H])C([H])([H])C([H])([H])N1* 0.000 description 1
- 125000005057 dihydrothienyl group Chemical group S1C(CC=C1)* 0.000 description 1
- 125000000532 dioxanyl group Chemical group 0.000 description 1
- 125000005879 dioxolanyl group Chemical group 0.000 description 1
- SXZIXHOMFPUIRK-UHFFFAOYSA-N diphenylmethanimine Chemical compound C=1C=CC=CC=1C(=N)C1=CC=CC=C1 SXZIXHOMFPUIRK-UHFFFAOYSA-N 0.000 description 1
- SEBARIVPCNBHKO-UHFFFAOYSA-N dipyridin-2-ylmethyl carbamate Chemical compound C=1C=CC=NC=1C(OC(=O)N)C1=CC=CC=N1 SEBARIVPCNBHKO-UHFFFAOYSA-N 0.000 description 1
- 125000005883 dithianyl group Chemical group 0.000 description 1
- 125000005411 dithiolanyl group Chemical group S1SC(CC1)* 0.000 description 1
- POULHZVOKOAJMA-UHFFFAOYSA-M dodecanoate Chemical compound CCCCCCCCCCCC([O-])=O POULHZVOKOAJMA-UHFFFAOYSA-M 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 150000002081 enamines Chemical class 0.000 description 1
- YQGOJNYOYNNSMM-UHFFFAOYSA-N eosin Chemical compound [Na+].OC(=O)C1=CC=CC=C1C1=C2C=C(Br)C(=O)C(Br)=C2OC2=C(Br)C(O)=C(Br)C=C21 YQGOJNYOYNNSMM-UHFFFAOYSA-N 0.000 description 1
- 150000002118 epoxides Chemical class 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 125000005678 ethenylene group Chemical group [H]C([*:1])=C([H])[*:2] 0.000 description 1
- 125000001033 ether group Chemical group 0.000 description 1
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 description 1
- 125000000219 ethylidene group Chemical group [H]C(=[*])C([H])([H])[H] 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 210000003722 extracellular fluid Anatomy 0.000 description 1
- 210000003608 fece Anatomy 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- FGIVSGPRGVABAB-UHFFFAOYSA-N fluoren-9-ylmethyl hydrogen carbonate Chemical compound C1=CC=C2C(COC(=O)O)C3=CC=CC=C3C2=C1 FGIVSGPRGVABAB-UHFFFAOYSA-N 0.000 description 1
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- RGEAONPOJJBMHO-UHFFFAOYSA-N furan-2-ylmethyl carbamate Chemical compound NC(=O)OCC1=CC=CO1 RGEAONPOJJBMHO-UHFFFAOYSA-N 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- JFCQEDHGNNZCLN-UHFFFAOYSA-N glutaric acid Chemical compound OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 125000006341 heptafluoro n-propyl group Chemical group FC(F)(F)C(F)(F)C(F)(F)* 0.000 description 1
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 1
- 125000005241 heteroarylamino group Chemical group 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
- 150000004687 hexahydrates Chemical class 0.000 description 1
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 125000006038 hexenyl group Chemical group 0.000 description 1
- 125000005980 hexynyl group Chemical group 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- HSNUXDIQZKIQRR-UHFFFAOYSA-N hydroxy-imino-bis(phenylmethoxy)-$l^{5}-phosphane Chemical compound C=1C=CC=CC=1COP(=O)(N)OCC1=CC=CC=C1 HSNUXDIQZKIQRR-UHFFFAOYSA-N 0.000 description 1
- QWMUDOFWQWBHFI-UHFFFAOYSA-N hydroxy-imino-diphenoxy-$l^{5}-phosphane Chemical compound C=1C=CC=CC=1OP(=O)(N)OC1=CC=CC=C1 QWMUDOFWQWBHFI-UHFFFAOYSA-N 0.000 description 1
- RIGIWEGXTTUCIQ-UHFFFAOYSA-N hydroxy-imino-diphenyl-$l^{5}-phosphane Chemical compound C=1C=CC=CC=1P(=O)(N)C1=CC=CC=C1 RIGIWEGXTTUCIQ-UHFFFAOYSA-N 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000003364 immunohistochemistry Methods 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 1
- 125000004594 isoindolinyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 229940001447 lactate Drugs 0.000 description 1
- JYTUSYBCFIZPBE-AMTLMPIISA-M lactobionate Chemical compound [O-]C(=O)[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O JYTUSYBCFIZPBE-AMTLMPIISA-M 0.000 description 1
- 229940099584 lactobionate Drugs 0.000 description 1
- 229940070765 laurate Drugs 0.000 description 1
- 229940058352 levulinate Drugs 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 210000002751 lymph Anatomy 0.000 description 1
- 230000002934 lysing effect Effects 0.000 description 1
- 150000002678 macrocyclic compounds Chemical class 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical group CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 description 1
- RMIODHQZRUFFFF-UHFFFAOYSA-M methoxyacetate Chemical compound COCC([O-])=O RMIODHQZRUFFFF-UHFFFAOYSA-M 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- CXHHBNMLPJOKQD-UHFFFAOYSA-M methyl carbonate Chemical compound COC([O-])=O CXHHBNMLPJOKQD-UHFFFAOYSA-M 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- NYEBKUUITGFJAK-UHFFFAOYSA-N methylsulfanylmethanethioic s-acid Chemical compound CSC(O)=S NYEBKUUITGFJAK-UHFFFAOYSA-N 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 238000001531 micro-dissection Methods 0.000 description 1
- 238000001000 micrograph Methods 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- CQDGTJPVBWZJAZ-UHFFFAOYSA-N monoethyl carbonate Chemical compound CCOC(O)=O CQDGTJPVBWZJAZ-UHFFFAOYSA-N 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- YNTOKMNHRPSGFU-UHFFFAOYSA-N n-Propyl carbamate Chemical compound CCCOC(N)=O YNTOKMNHRPSGFU-UHFFFAOYSA-N 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-M naphthalene-2-sulfonate Chemical compound C1=CC=CC2=CC(S(=O)(=O)[O-])=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-M 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 125000005893 naphthalimidyl group Chemical group 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 210000002445 nipple Anatomy 0.000 description 1
- SFDJOSRHYKHMOK-UHFFFAOYSA-N nitramide Chemical compound N[N+]([O-])=O SFDJOSRHYKHMOK-UHFFFAOYSA-N 0.000 description 1
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 1
- XKLJHFLUAHKGGU-UHFFFAOYSA-N nitrous amide Chemical compound ON=N XKLJHFLUAHKGGU-UHFFFAOYSA-N 0.000 description 1
- BDJRBEYXGGNYIS-UHFFFAOYSA-N nonanedioic acid Chemical compound OC(=O)CCCCCCCC(O)=O BDJRBEYXGGNYIS-UHFFFAOYSA-N 0.000 description 1
- 125000001736 nosyl group Chemical group S(=O)(=O)(C1=CC=C([N+](=O)[O-])C=C1)* 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 125000005889 octahydrochromenyl group Chemical group 0.000 description 1
- 125000005890 octahydroisochromenyl group Chemical group 0.000 description 1
- 125000004365 octenyl group Chemical group C(=CCCCCCC)* 0.000 description 1
- 125000005069 octynyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C#C* 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-M oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC([O-])=O ZQPPMHVWECSIRJ-KTKRTIGZSA-M 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 210000003463 organelle Anatomy 0.000 description 1
- 125000005882 oxadiazolinyl group Chemical group 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000005880 oxathiolanyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000003551 oxepanyl group Chemical group 0.000 description 1
- 125000003585 oxepinyl group Chemical group 0.000 description 1
- 125000003566 oxetanyl group Chemical group 0.000 description 1
- 125000000466 oxiranyl group Chemical group 0.000 description 1
- 125000004043 oxo group Chemical group O=* 0.000 description 1
- AUONHKJOIZSQGR-UHFFFAOYSA-N oxophosphane Chemical compound P=O AUONHKJOIZSQGR-UHFFFAOYSA-N 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 125000006505 p-cyanobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C#N)C([H])([H])* 0.000 description 1
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 125000004817 pentamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 125000005981 pentynyl group Chemical group 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Chemical compound [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- JRKICGRDRMAZLK-UHFFFAOYSA-L peroxydisulfate Chemical compound [O-]S(=O)(=O)OOS([O-])(=O)=O JRKICGRDRMAZLK-UHFFFAOYSA-L 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 125000004934 phenanthridinyl group Chemical group C1(=CC=CC2=NC=C3C=CC=CC3=C12)* 0.000 description 1
- 125000001791 phenazinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3N=C12)* 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 125000001484 phenothiazinyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 description 1
- 125000001644 phenoxazinyl group Chemical group C1(=CC=CC=2OC3=CC=CC=C3NC12)* 0.000 description 1
- LCPDWSOZIOUXRV-UHFFFAOYSA-N phenoxyacetic acid Chemical compound OC(=O)COC1=CC=CC=C1 LCPDWSOZIOUXRV-UHFFFAOYSA-N 0.000 description 1
- BSCCSDNZEIHXOK-UHFFFAOYSA-N phenyl carbamate Chemical compound NC(=O)OC1=CC=CC=C1 BSCCSDNZEIHXOK-UHFFFAOYSA-N 0.000 description 1
- FAQJJMHZNSSFSM-UHFFFAOYSA-N phenylglyoxylic acid Chemical compound OC(=O)C(=O)C1=CC=CC=C1 FAQJJMHZNSSFSM-UHFFFAOYSA-N 0.000 description 1
- ABOYDMHGKWRPFD-UHFFFAOYSA-N phenylmethanesulfonamide Chemical compound NS(=O)(=O)CC1=CC=CC=C1 ABOYDMHGKWRPFD-UHFFFAOYSA-N 0.000 description 1
- NIXKBAZVOQAHGC-UHFFFAOYSA-N phenylmethanesulfonic acid Chemical compound OS(=O)(=O)CC1=CC=CC=C1 NIXKBAZVOQAHGC-UHFFFAOYSA-N 0.000 description 1
- AFDMODCXODAXLC-UHFFFAOYSA-N phenylmethanimine Chemical compound N=CC1=CC=CC=C1 AFDMODCXODAXLC-UHFFFAOYSA-N 0.000 description 1
- 150000008298 phosphoramidates Chemical class 0.000 description 1
- 125000005498 phthalate group Chemical class 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 125000005545 phthalimidyl group Chemical group 0.000 description 1
- 229940075930 picrate Drugs 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-M picrate anion Chemical compound [O-]C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-M 0.000 description 1
- WLJVNTCWHIRURA-UHFFFAOYSA-M pimelate(1-) Chemical compound OC(=O)CCCCCC([O-])=O WLJVNTCWHIRURA-UHFFFAOYSA-M 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-M pivalate Chemical compound CC(C)(C)C([O-])=O IUGYQRQAERSCNH-UHFFFAOYSA-M 0.000 description 1
- 229950010765 pivalate Drugs 0.000 description 1
- 125000005547 pivalate group Chemical group 0.000 description 1
- 230000003169 placental effect Effects 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- OCAAZRFBJBEVPS-UHFFFAOYSA-N prop-2-enyl carbamate Chemical compound NC(=O)OCC=C OCAAZRFBJBEVPS-UHFFFAOYSA-N 0.000 description 1
- ZNZJJSYHZBXQSM-UHFFFAOYSA-N propane-2,2-diamine Chemical compound CC(C)(N)N ZNZJJSYHZBXQSM-UHFFFAOYSA-N 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- RWUGBYOALBYTGU-UHFFFAOYSA-N pyridin-4-ylmethyl carbamate Chemical compound NC(=O)OCC1=CC=NC=C1 RWUGBYOALBYTGU-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- FLCPORVHXQFBHT-UHFFFAOYSA-N quinolin-8-yl carbamate Chemical compound C1=CN=C2C(OC(=O)N)=CC=CC2=C1 FLCPORVHXQFBHT-UHFFFAOYSA-N 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- YBKWIGSMABMNJZ-UHFFFAOYSA-N s-(2,3,4,5,6-pentachlorophenyl)thiohydroxylamine Chemical compound NSC1=C(Cl)C(Cl)=C(Cl)C(Cl)=C1Cl YBKWIGSMABMNJZ-UHFFFAOYSA-N 0.000 description 1
- RTKRAORYZUBVGQ-UHFFFAOYSA-N s-(2,4-dinitrophenyl)thiohydroxylamine Chemical compound NSC1=CC=C([N+]([O-])=O)C=C1[N+]([O-])=O RTKRAORYZUBVGQ-UHFFFAOYSA-N 0.000 description 1
- LOVVSIULYJABJF-UHFFFAOYSA-N s-(2-nitrophenyl)thiohydroxylamine Chemical compound NSC1=CC=CC=C1[N+]([O-])=O LOVVSIULYJABJF-UHFFFAOYSA-N 0.000 description 1
- BDEZGPKAMAVGBE-UHFFFAOYSA-N s-(3-nitropyridin-2-yl)thiohydroxylamine Chemical compound NSC1=NC=CC=C1[N+]([O-])=O BDEZGPKAMAVGBE-UHFFFAOYSA-N 0.000 description 1
- DAXSYWBYJZACTA-UHFFFAOYSA-N s-(4-methoxy-2-nitrophenyl)thiohydroxylamine Chemical compound COC1=CC=C(SN)C([N+]([O-])=O)=C1 DAXSYWBYJZACTA-UHFFFAOYSA-N 0.000 description 1
- LOFZYSZWOLKUGE-UHFFFAOYSA-N s-benzyl carbamothioate Chemical compound NC(=O)SCC1=CC=CC=C1 LOFZYSZWOLKUGE-UHFFFAOYSA-N 0.000 description 1
- MAGSSGQAJNNDLU-UHFFFAOYSA-N s-phenylthiohydroxylamine Chemical compound NSC1=CC=CC=C1 MAGSSGQAJNNDLU-UHFFFAOYSA-N 0.000 description 1
- PIDYQAYNSQSDQY-UHFFFAOYSA-N s-tritylthiohydroxylamine Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(SN)C1=CC=CC=C1 PIDYQAYNSQSDQY-UHFFFAOYSA-N 0.000 description 1
- BPELEZSCHIEMAE-UHFFFAOYSA-N salicylaldehyde imine Chemical compound OC1=CC=CC=C1C=N BPELEZSCHIEMAE-UHFFFAOYSA-N 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 210000003296 saliva Anatomy 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 229940116351 sebacate Drugs 0.000 description 1
- CXMXRPHRNRROMY-UHFFFAOYSA-L sebacate(2-) Chemical compound [O-]C(=O)CCCCCCCCC([O-])=O CXMXRPHRNRROMY-UHFFFAOYSA-L 0.000 description 1
- 238000000680 secondary ion mass spectrometry imaging Methods 0.000 description 1
- 210000000582 semen Anatomy 0.000 description 1
- 238000012163 sequencing technique Methods 0.000 description 1
- 239000003352 sequestering agent Substances 0.000 description 1
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000003797 solvolysis reaction Methods 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- TYFQFVWCELRYAO-UHFFFAOYSA-L suberate(2-) Chemical compound [O-]C(=O)CCCCCCC([O-])=O TYFQFVWCELRYAO-UHFFFAOYSA-L 0.000 description 1
- 125000005017 substituted alkenyl group Chemical group 0.000 description 1
- 125000004426 substituted alkynyl group Chemical group 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 1
- 125000000565 sulfonamide group Chemical group 0.000 description 1
- 150000003459 sulfonic acid esters Chemical class 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 210000004243 sweat Anatomy 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- XKXIQBVKMABYQJ-UHFFFAOYSA-M tert-butyl carbonate Chemical compound CC(C)(C)OC([O-])=O XKXIQBVKMABYQJ-UHFFFAOYSA-M 0.000 description 1
- XBXCNNQPRYLIDE-UHFFFAOYSA-N tert-butylcarbamic acid Chemical compound CC(C)(C)NC(O)=O XBXCNNQPRYLIDE-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005887 tetrahydrobenzofuranyl group Chemical group 0.000 description 1
- 125000005886 tetrahydrobenzothienyl group Chemical group 0.000 description 1
- 125000005888 tetrahydroindolyl group Chemical group 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000003507 tetrahydrothiofenyl group Chemical group 0.000 description 1
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- 125000005247 tetrazinyl group Chemical group N1=NN=NC(=C1)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000005305 thiadiazolinyl group Chemical group 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000005458 thianyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000001583 thiepanyl group Chemical group 0.000 description 1
- 125000003777 thiepinyl group Chemical group 0.000 description 1
- 125000002053 thietanyl group Chemical group 0.000 description 1
- 125000001730 thiiranyl group Chemical group 0.000 description 1
- 150000003568 thioethers Chemical group 0.000 description 1
- UIERETOOQGIECD-ONEGZZNKSA-N tiglic acid Chemical compound C\C=C(/C)C(O)=O UIERETOOQGIECD-ONEGZZNKSA-N 0.000 description 1
- LMYRWZFENFIFIT-UHFFFAOYSA-N toluene-4-sulfonamide Chemical compound CC1=CC=C(S(N)(=O)=O)C=C1 LMYRWZFENFIFIT-UHFFFAOYSA-N 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 125000005881 triazolinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 229940066528 trichloroacetate Drugs 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- KAKQVSNHTBLJCH-UHFFFAOYSA-N trifluoromethanesulfonimidic acid Chemical compound NS(=O)(=O)C(F)(F)F KAKQVSNHTBLJCH-UHFFFAOYSA-N 0.000 description 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 1
- BZVJOYBTLHNRDW-UHFFFAOYSA-N triphenylmethanamine Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(N)C1=CC=CC=C1 BZVJOYBTLHNRDW-UHFFFAOYSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- WFKWXMTUELFFGS-UHFFFAOYSA-N tungsten Chemical compound [W] WFKWXMTUELFFGS-UHFFFAOYSA-N 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
- 239000010937 tungsten Substances 0.000 description 1
- 229960003732 tyramine Drugs 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- LVLANIHJQRZTPY-UHFFFAOYSA-N vinyl carbamate Chemical compound NC(=O)OC=C LVLANIHJQRZTPY-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/531—Production of immunochemical test materials
- G01N33/532—Production of labelled immunochemicals
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/531—Production of immunochemical test materials
- G01N33/532—Production of labelled immunochemicals
- G01N33/535—Production of labelled immunochemicals with enzyme label or co-enzymes, co-factors, enzyme inhibitors or enzyme substrates
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/536—Immunoassay; Biospecific binding assay; Materials therefor with immune complex formed in liquid phase
- G01N33/542—Immunoassay; Biospecific binding assay; Materials therefor with immune complex formed in liquid phase with steric inhibition or signal modification, e.g. fluorescent quenching
Definitions
- Catalyzed reporter deposition is a method of signal amplification useful in assaying biological samples for analyte detection. See U.S. Pat. Nos. 5,731,158, 5,583,001, and 5,196,306 which are hereby incorporated by reference.
- the CARD method utilizes an analyte-dependent enzyme activation system (ADEAS) to catalyze the deposition of reporter groups (e.g., fluorescein, biotin) onto a receptor, the receptor being part of or added to a surface in contact with the components of the assay.
- reporter groups e.g., fluorescein, biotin
- the peroxidase oxidizes a hydrogen-donating moiety of a substrate conjugate comprising a labeled compound.
- a reactive intermediate is formed, which binds covalently with electron-rich residues near the receptor of the reactive intermediate.
- Hydrogen-donating moieties that are reactive with peroxidase enzymes include substituted phenols, such as tyramides, tyramines, and p-hydroxycinnamoyl-containing compounds.
- Specific reporters attached to the conjugate can be detected by fluorescence or light microscopy at the specific site of covalent attachment.
- the macrocycle 1,4,7,10-tetraazacyclododecane-1,4,7-tetraacetic acid is a chelating agent that can be employed in constructing compounds useful in the CARD method of detecting analytes in biological samples.
- the chelated form of DOTA can serve as a reporter moiety and be linked to reactive molecules (e.g., phenols) to form a compound that can bind to specific biological target molecules for analyte detection.
- the present disclosure describes DOTA-tyramide, DOTA-tyramine, and DOTA-cinnamamide compounds, salts, and chelate complexes thereof that are useful for site-specific binding and analyte detection.
- the DOTA containing compounds offer advantages over existing reporter compounds because the DOTA moiety can be detected directly (e.g., by mass spectrometry based imaging microscopy).
- G is a chelating moiety
- R 1 is substituted or unsubstituted alkylene, a bond, —O—, —S—, or —NR A —;
- R 2 is a bond, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
- X 1 is a bond or N
- X is O or S
- R 3 is hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, or a nitrogen protecting group
- R 4 is substituted or unsubstituted C 2 -C 6 heteroaliphatic, substituted or unsubstituted C 2 -C 6 alkylene, substituted or unsubstituted C 2 -C 6 alkenylene, or substituted or unsubstituted C 2 -C 6 alkynylene;
- R 5 is hydrogen, halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —N(R A ) 2 , or —OR A ;
- R 6 is hydrogen, halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —N(R A ) 2 , or —OR A ;
- R 7 is hydrogen, halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —N(R A ) 2 , or —OR A ;
- R 8 is hydrogen, halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —N(R A ) 2 , or —OR A ; and each occurrence of R A is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, a nitrogen protecting group when attached to a nitrogen atom, or an oxygen protecting group when attached to an oxygen atom, or two R
- the compound of Formula (I) is a compound of Formula (I-a):
- R 1 is substituted or unsubstituted alkylene, a bond, —O—, —S—, or —NR A ;
- R 2 is substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
- X is O or S
- R 3 is hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, or a nitrogen protecting group
- R 4 is substituted or unsubstituted C 2 -C 6 heteroaliphatic, substituted or unsubstituted C 2 -C 6 alkylene, substituted or unsubstituted C 2 -C 6 alkenylene, or substituted or unsubstituted C 2 -C 6 alkynylene;
- R 5 is hydrogen, halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —N(R A ) 2 , or —OR A ;
- R 6 is hydrogen, halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —N(R A ) 2 , or —OR A ;
- R 7 is hydrogen, halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —N(R A ) 2 , or —OR A ;
- R 8 is hydrogen, halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —N(R A ) 2 , or —OR A ; and
- each occurrence of R A is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, a nitrogen protecting group when attached to a nitrogen atom, or an oxygen protecting group when attached to an oxygen atom, or two R A groups are joined to form a substituted or unsubstituted heterocyclic ring.
- Exemplary compounds of Formula (I) include, but are not limited to:
- salts comprising a compound of Formula (I).
- the salt comprises a metal counterion (e.g., bismuth, lead, yttrium, cadmium, mercury, actinium, thorium, strontium, or a lanthanide).
- the metal counterion is yttrium, praseodymium, or lutetium.
- chelate complexes comprising a compound of Formula (I), or a salt of a compound of Formula (I).
- the chelate complex is a trivalent complex.
- Exemplary chelate complexes comprising compounds of Formula (I) include, but are not limited to:
- analyte comprising reacting an enzyme (e.g., a peroxidase) with a chelate complex comprising a compound of Formula (I), or a salt thereof, to form an oxidized chelate complex; contacting the oxidized chelate complex with an biological sample; and detecting the analyte in the biological sample.
- an enzyme e.g., a peroxidase
- a chelate complex comprising a compound of Formula (I), or a salt thereof
- the method further comprises covalent binding of the oxidized chelate complex with the analyte.
- kits comprising a compound of Formula (I), or a salt thereof, or a chelate complex comprising a compound of Formula (I).
- the kit further comprises instructions for use.
- FIG. 1 is a series of micrographs showing results of CARD assays employing exemplary compounds of the disclosure.
- the expression of the intermediate filament protein nestin was detected in normal human kidney podocytes using a goat anti-nestin polyclonal antibody with a rabbit anti-goat secondary horseradish peroxidase/3,3′-diaminobenzidine (DAB) chromogenic assay and standard light microscopy ( FIG. 1A ).
- the chromogenic signal for nestin expression was not seen with negative control conditions including without anti-nestin primary antibody ( FIG. 1C ) or without secondary antibody ( FIG. 1B ).
- DAB was replaced with exemplary compounds 1, 2, and 3 complexed to Pr 3+ ; ( FIG. 1E , FIG.
- FIG. 2 is a series of images showing detection of compounds 1 and 3 using a mass spectrometry imaging device.
- the expression of the cytokeratin 7 (CK7) intermediate filament protein was detected in normal human placenta sections (4 ⁇ m; formalin fixation and paraffin embedded) with immunohistochemistry using a mouse anti-CK7 primary antibody followed by an anti-mouse secondary horseradish peroxidase/3,3′-diaminobenzidine (DAB) chromogenic assay and a standard light microscope (H).
- DAB was replaced with compound 1 or 3 chelating Pr 3+ ( FIG. 2A , FIG. 2B ) or Y 3+ ( FIG. 2C , FIG.
- 2I refers to the syncytiotrophoblast layer of placenta.
- compounds 1 and 3 not chelated to a metal were not recognized by the mass spectrometry imaging device and therefore specific CK7 signal was not seen using these control assay conditions ( FIG. 2E , FIG. 2F ).
- the dilution of the compound is shown parenthetically.
- Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and/or diastereomers.
- the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer.
- Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses.
- HPLC high pressure liquid chromatography
- a single bond where the stereochemistry of the moieties immediately attached thereto is not specified, is absent or a single bond, and or is a single or double bond.
- structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
- compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, replacement of 19 F with 18 F, or the replacement of 12 C with 13 C or 14 C are within the scope of the disclosure.
- Such compounds are useful, for example, as analytical tools or probes in biological assays.
- C 1-6 alkyl is intended to encompass, C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 , and C 5-6 alkyl.
- aliphatic refers to alkyl, alkenyl, alkynyl, and carbocyclic groups.
- heteroaliphatic refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.
- alkyl refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 10 carbon atoms (“C 1-10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C 1-9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C 1-3 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C 1-7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C 1-6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C 1-5 alkyl”).
- an alkyl group has 1 to 4 carbon atoms (“C 1-4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C 1-3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C 1-2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C 1 alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C 2-6 alkyl”).
- C 1-6 alkyl groups include methyl (C 1 ), ethyl (C 2 ), propyl (C 3 ) (e.g., n-propyl, isopropyl), butyl (C 4 ) (e.g., n-butyl, tert-butyl, sec-butyl, iso-butyl), pentyl (C 5 ) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tertiary amyl), and hexyl (C 6 ) (e.g., n-hexyl).
- alkyl groups include n-heptyl (C 7 ), n-octyl (C 8 ), and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents (e.g., halogen, such as F).
- substituents e.g., halogen, such as F
- the alkyl group is an unsubstituted C 1-10 alkyl (such as unsubstituted C 1-6 alkyl, e.g., —CH 3 (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)), unsubstituted butyl (Bu, e.g., unsubstituted n-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec-Bu), unsubstituted isobutyl (i-Bu)).
- the alkyl group is a substituted C 1-10 alkyl (such as substituted C 1-6 alkyl, e.g.,
- haloalkyl is a substituted alkyl group, wherein one or more of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo.
- the haloalkyl moiety has 1 to 8 carbon atoms (“C 1-8 haloalkyl”).
- the haloalkyl moiety has 1 to 6 carbon atoms (“C 1-6 haloalkyl”).
- the haloalkyl moiety has 1 to 4 carbon atoms (“C 1-4 haloalkyl”).
- the haloalkyl moiety has 1 to 3 carbon atoms (“C 1-3 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 2 carbon atoms (“C 1-2 haloalkyl”). Examples of haloalkyl groups include —CHF 2 , —CH 2 F, —CF 3 , —CH 2 CF 3 , —CF 2 CF 3 , —CF 2 CF 2 CF 3 , —CCl 3 , —CFCl 2 , —CF 2 Cl, and the like.
- heteroalkyl refers to an alkyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain.
- a heteroalkyl group refers to a saturated group having from 1 to 20 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1-20 alkyl”).
- a heteroalkyl group is a saturated group having 1 to 18 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1-18 alkyl”).
- a heteroalkyl group is a saturated group having 1 to 16 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1-16 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 14 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1-14 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 12 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1-12 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 10 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1-10 alkyl”).
- a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1-8 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1-6 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC 1-4 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain (“heteroC 1-3 alkyl”).
- a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain (“heteroC 1-2 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroC 1 alkyl”). In some embodiments, the heteroalkyl group defined herein is a partially unsaturated group having 1 or more heteroatoms within the parent chain and at least one unsaturated carbon, such as a carbonyl group. For example, a heteroalkyl group may comprise an amide or ester functionality in its parent chain such that one or more carbon atoms are unsaturated carbonyl groups.
- each instance of a heteroalkyl group is independently unsubstituted (an “unsubstituted heteroalkyl”) or substituted (a “substituted heteroalkyl”) with one or more substituents.
- the heteroalkyl group is an unsubstituted heteroC 1-20 alkyl.
- the heteroalkyl group is an unsubstituted heteroC 1-10 alkyl.
- the heteroalkyl group is a substituted heteroC 1-20 alkyl.
- the heteroalkyl group is an unsubstituted heteroC 1-10 alkyl.
- alkenyl refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds).
- an alkenyl group has 2 to 9 carbon atoms (“C 2-9 alkenyl”).
- an alkenyl group has 2 to 8 carbon atoms (“C 2-8 alkenyl”).
- an alkenyl group has 2 to 7 carbon atoms (“C 2-7 alkenyl”).
- an alkenyl group has 2 to 6 carbon atoms (“C 2-6 alkenyl”).
- an alkenyl group has 2 to 5 carbon atoms (“C 2-5 alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C 2-4 alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C 2-3 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C 2 alkenyl”).
- the one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl).
- Examples of C 2-4 alkenyl groups include ethenyl (C 2 ), 1-propenyl (C 3 ), 2-propenyl (C 3 ), 1-butenyl (C 4 ), 2-butenyl (C 4 ), butadienyl (C 4 ), and the like.
- Examples of C 2-6 alkenyl groups include the aforementioned C 2-4 alkenyl groups as well as pentenyl (C 5 ), pentadienyl (C 5 ), hexenyl (C 6 ), and the like. Additional examples of alkenyl include heptenyl (C 7 ), octenyl (C 8 ), octatrienyl (C 8 ), and the like.
- each instance of an alkenyl group is independently unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents.
- the alkenyl group is an unsubstituted C 2-10 alkenyl.
- the alkenyl group is a substituted C 2-10 alkenyl.
- a C ⁇ C double bond for which the stereochemistry is not specified e.g., —CH ⁇ CHCH 3 or
- heteroalkenyl refers to an alkenyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain.
- a heteroalkenyl group refers to a group having from 2 to 10 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 2-10 alkenyl”).
- a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 2-9 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 2-8 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 2-7 alkenyl”).
- a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 2-6 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC 2-5 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC 2-4 alkenyl”).
- a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“heteroC 2-3 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC 2-6 alkenyl”). Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an “unsubstituted heteroalkenyl”) or substituted (a “substituted heteroalkenyl”) with one or more substituents. In certain embodiments, the heteroalkenyl group is an unsubstituted heteroC 2-10 alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroC 2-10 alkenyl.
- alkynyl refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) (“C 2-10 alkynyl”).
- an alkynyl group has 2 to 9 carbon atoms (“C 2-9 alkynyl”).
- an alkynyl group has 2 to 8 carbon atoms (“C 2-8 alkynyl”).
- an alkynyl group has 2 to 7 carbon atoms (“C 2-7 alkynyl”).
- an alkynyl group has 2 to 6 carbon atoms (“C 2-6 alkynyl”).
- an alkynyl group has 2 to 5 carbon atoms (“C 2-5 alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C 2-4 alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C 2-3 alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C 2 alkynyl”).
- the one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl).
- Examples of C 2-4 alkynyl groups include, without limitation, ethynyl (C 2 ), 1-propynyl (C 3 ), 2-propynyl (C 3 ), 1-butynyl (C 4 ), 2-butynyl (C 4 ), and the like.
- Examples of C 2-6 alkenyl groups include the aforementioned C 2-4 alkynyl groups as well as pentynyl (C 5 ), hexynyl (C 6 ), and the like. Additional examples of alkynyl include heptynyl (C 7 ), octynyl (C 8 ), and the like.
- each instance of an alkynyl group is independently unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents.
- the alkynyl group is an unsubstituted C 2-10 alkynyl.
- the alkynyl group is a substituted C 2-10 alkynyl.
- heteroalkynyl refers to an alkynyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain.
- a heteroalkynyl group refers to a group having from 2 to 10 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 2-10 alkynyl”).
- a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 2-9 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 2-8 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 2-7 alkynyl”).
- a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 2-6 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC 2-5 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC 2-4 alkynyl”).
- a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“heteroC 2-3 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC 2-6 alkynyl”). Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an “unsubstituted heteroalkynyl”) or substituted (a “substituted heteroalkynyl”) with one or more substituents. In certain embodiments, the heteroalkynyl group is an unsubstituted heteroC 2-10 alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroC 2-10 alkynyl.
- carbocyclyl refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms (“C 3-14 carbocyclyl”) and zero heteroatoms in the non-aromatic ring system.
- a carbocyclyl group has 3 to 10 ring carbon atoms (“C 3-10 carbocyclyl”).
- a carbocyclyl group has 3 to 8 ring carbon atoms (“C 3-8 carbocyclyl”).
- a carbocyclyl group has 3 to 7 ring carbon atoms (“C 3-7 carbocyclyl”).
- a carbocyclyl group has 3 to 6 ring carbon atoms (“C 3-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms (“C 4-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C 5-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C 5-10 carbocyclyl”).
- Exemplary C 3-6 carbocyclyl groups include, without limitation, cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ), and the like.
- Exemplary C 3-8 carbocyclyl groups include, without limitation, the aforementioned C 3-6 carbocyclyl groups as well as cycloheptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (C 8 ), cyclooctenyl (C 8 ), bicyclo[2.2.1]heptanyl (C 7 ), bicyclo[2.2.2]octanyl (C 8 ), and the like.
- Exemplary C 3-10 carbocyclyl groups include, without limitation, the aforementioned C 3-8 carbocyclyl groups as well as cyclononyl (C 9 ), cyclononenyl (C 9 ), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C 9 ), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 ), and the like.
- the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and can be saturated or can contain one or more carbon-carbon double or triple bonds.
- Carbocyclyl also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system.
- each instance of a carbocyclyl group is independently unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents.
- the carbocyclyl group is an unsubstituted C 3-14 carbocyclyl.
- the carbocyclyl group is a substituted C 3-14 carbocyclyl.
- “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 14 ring carbon atoms (“C 3-14 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms (“C 3-10 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C 3-8 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C 3-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms (“C 4-6 cycloalkyl”).
- a cycloalkyl group has 5 to 6 ring carbon atoms (“C 5-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C 5-10 cycloalkyl”). Examples of C 5-6 cycloalkyl groups include cyclopentyl (C 5 ) and cyclohexyl (C 5 ). Examples of C 3-6 cycloalkyl groups include the aforementioned C 5-6 cycloalkyl groups as well as cyclopropyl (C 3 ) and cyclobutyl (C 4 ).
- C 3-8 cycloalkyl groups include the aforementioned C 3-6 cycloalkyl groups as well as cycloheptyl (C 7 ) and cyclooctyl (C 8 ).
- each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents.
- the cycloalkyl group is an unsubstituted C 3-14 cycloalkyl.
- the cycloalkyl group is a substituted C 3-14 cycloalkyl.
- heterocyclyl refers to a radical of a 3- to 14-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3-14 membered heterocyclyl”).
- heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits.
- a heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g., a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”)), and can be saturated or can contain one or more carbon-carbon double or triple bonds.
- Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings.
- Heterocyclyl also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system.
- each instance of heterocyclyl is independently unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents.
- the heterocyclyl group is an unsubstituted 3-14 membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3-14 membered heterocyclyl.
- a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heterocyclyl”).
- a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”).
- a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”).
- the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
- the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
- the 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
- Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azirdinyl, oxiranyl, and thiiranyl.
- Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azetidinyl, oxetanyl, and thietanyl.
- Exemplary 5-membered heterocyclyl groups containing 1 heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione.
- Exemplary 5-membered heterocyclyl groups containing 2 heteroatoms include, without limitation, dioxolanyl, oxathiolanyl and dithiolanyl.
- Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl.
- Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl.
- Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl.
- Exemplary 6-membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazinyl.
- Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl.
- Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl.
- bicyclic heterocyclyl groups include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H-benzo[e][1,4-
- aryl refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 ⁇ electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C 6-14 aryl”).
- an aryl group has 6 ring carbon atoms (“C 6 aryl”; e.g., phenyl).
- an aryl group has 10 ring carbon atoms (“C 10 aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl).
- an aryl group has 14 ring carbon atoms (“C 14 aryl”; e.g., anthracyl).
- Aryl also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system.
- each instance of an aryl group is independently unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents.
- the aryl group is an unsubstituted C 6-14 aryl.
- the aryl group is a substituted C 6-14 aryl.
- Alkyl is a subset of “alkyl” and refers to an alkyl group substituted by an aryl group, wherein the point of attachment is on the alkyl moiety.
- heteroaryl refers to a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 ⁇ electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-14 membered heteroaryl”).
- the point of attachment can be a carbon or nitrogen atom, as valency permits.
- Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings.
- Heteroaryl includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused polycyclic (aryl/heteroaryl) ring system.
- Polycyclic heteroaryl groups wherein one ring does not contain a heteroatom e.g., indolyl, quinolinyl, carbazolyl, and the like
- the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).
- a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”).
- a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”).
- a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”).
- the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
- the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
- the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
- each instance of a heteroaryl group is independently unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents.
- the heteroaryl group is an unsubstituted 5-14 membered heteroaryl.
- the heteroaryl group is a substituted 5-14 membered heteroaryl.
- Exemplary 5-membered heteroaryl groups containing 1 heteroatom include, without limitation, pyrrolyl, furanyl, and thiophenyl.
- Exemplary 5-membered heteroaryl groups containing 2 heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl.
- Exemplary 5-membered heteroaryl groups containing 3 heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl.
- Exemplary 5-membered heteroaryl groups containing 4 heteroatoms include, without limitation, tetrazolyl.
- Exemplary 6-membered heteroaryl groups containing 1 heteroatom include, without limitation, pyridinyl.
- Exemplary 6-membered heteroaryl groups containing 2 heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl.
- Exemplary 6-membered heteroaryl groups containing 3 or 4 heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively.
- Exemplary 7-membered heteroaryl groups containing 1 heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl.
- Exemplary 5,6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl.
- Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.
- Exemplary tricyclic heteroaryl groups include, without limitation, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl.
- Heteroaralkyl is a subset of “alkyl” and refers to an alkyl group substituted by a heteroaryl group, wherein the point of attachment is on the alkyl moiety.
- unsaturated or “partially unsaturated” refers to a moiety that includes at least one double or triple bond.
- saturated refers to a moiety that does not contain a double or triple bond, i.e., the moiety only contains single bonds.
- alkylene is the divalent moiety of alkyl
- alkenylene is the divalent moiety of alkenyl
- alkynylene is the divalent moiety of alkynyl
- heteroalkylene is the divalent moiety of heteroalkyl
- heteroalkenylene is the divalent moiety of heteroalkenyl
- heteroalkynylene is the divalent moiety of heteroalkynyl
- carbocyclylene is the divalent moiety of carbocyclyl
- heterocyclylene is the divalent moiety of heterocyclyl
- arylene is the divalent moiety of aryl
- heteroarylene is the divalent moiety of heteroaryl.
- a group is optionally substituted unless expressly provided otherwise.
- the term “optionally substituted” refers to being substituted or unsubstituted.
- alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted.
- Optionally substituted refers to a group which may be substituted or unsubstituted (e.g., “substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted” alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or “unsubstituted” heteroalkyl, “substituted” or “unsubstituted” heteroalkenyl, “substituted” or “unsubstituted” heteroalkynyl, “substituted” or “unsubstituted” carbocyclyl, “substituted” or “unsubstituted” heterocyclyl, “substituted” or “unsubstituted” aryl or “substituted” or “unsubstituted” heteroaryl group).
- substituted means that at least one hydrogen present on a group is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction.
- a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position.
- substituted is contemplated to include substitution with all permissible substituents of organic compounds, and includes any of the substituents described herein that results in the formation of a stable compound.
- the present invention contemplates any and all such combinations in order to arrive at a stable compound.
- heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety.
- the invention is not intended to be limited in any manner by the exemplary substituents described herein.
- Exemplary carbon atom substituents include, but are not limited to, halogen, —CN, —NO 2 , —N 3 , —SO 2 H, —SO 3 H, —OH, —OR aa , —ON(R bb ) 2 , —N(R bb ) 2 , N(R bb ) 3 X ⁇ , —N(OR cc )R bb , —SH, —SR aa , —SSR cc , —C( ⁇ O)R aa , —CO 2 H, —CHO, —C(OR cc ) 3 , —CO 2 R aa , —OC( ⁇ O)R aa , —OCO 2 R aa , —C( ⁇ O)N(R bb ) 2 , —OC( ⁇ O)N(R bb ) 2 , —NR bb C( ⁇ O
- each instance of R aa is, independently, selected from C 1-10 alkyl, C 1-10 perhaloalkyl C 2-10 alkenyl, C 2-10 alkynyl, heteroC 1-10 alkyl, heteroC 2-10 alkenyl, heteroC 2-10 alkynyl, C 3-10 carbocyclyl, 3-14 membered heterocyclyl C 6-14 aryl, and 5-14 membered heteroaryl or two R aa groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups;
- each instance of R bb is, independently, selected from hydrogen, —OH, —OR aa , —N(R cc ) 2 , —CN, —C( ⁇ O)R aa , —C( ⁇ O)N(R cc ) 2 , —CO 2 R aa , —SO 2 R aa , —C( ⁇ NR cc )OR aa , —C( ⁇ NR cc )N(R cc ) 2 , —SO 2 N(R cc ) 2 , —SO 2 R cc , —SO 2 OR cc , —SOR aa , —C( ⁇ S)N(R cc ) 2 , —C( ⁇ O)SR cc , —C( ⁇ S)SR cc , —P( ⁇ O)(R aa ) 2 , —P( ⁇ O)(OR cc ) 2
- each instance of R cc is, independently, selected from hydrogen, C 1-10 alkyl, C 1-10 perhaloalkyl, C 2-10 alkenyl C 2-10 alkynyl, heteroC 1-10 alkyl, heteroC 2-10 alkenyl, heteroC 2-10 alkynyl, C 3-10 carbocyclyl, 3-14 membered heterocyclyl C 6-14 aryl, and 5-14 membered heteroaryl, or two R cc groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups;
- each instance of R dd is, independently, selected from halogen, —CN, —NO 2 , —N 3 , —SO 2 H, —SO 3 H, —OH, —OR ee , —ON(R ff ) 2 , —N(R ff ) 2 , —N(R ff ) 3 + X ⁇ , —N(OR ee )R ff , —SH, —SR ee , —SSR ee , —C( ⁇ O)R ee , —CO 2 H, —CO 2 R ee , —OC( ⁇ O)R ee , —OCO 2 R ee , —C( ⁇ O)N(R ff ) 2 , —OC( ⁇ O)N(R ff ) 2 , —NR ff C( ⁇ O)R ee , —NR ff CO 2 R
- each instance of R ee is, independently, selected from C 1-6 alkyl, C 1-6 perhaloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, heteroC 1-6 alkyl, heteroC 2-6 alkenyl, heteroC 2-6 alkynyl, C 3-10 carbocyclyl, C 6-10 aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups;
- each instance of R ff is, independently, selected from hydrogen, C 1-6 alkyl, C 1-6 perhaloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, heteroC 1-6 alkyl, heteroC 2-6 alkenyl, heteroC 2-6 alkynyl, C 3-10 carbocyclyl, 3-10 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, or two R ff groups are joined to form a 3-10 membered heterocyclyl or 5-10 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups; and
- each instance of R gg is, independently, halogen, —CN, —NO 2 , —N 3 , —SO 2 H, —SO 3 H, —OH, —OC 1-6 alkyl, —ON(C 1-6 alkyl) 2 , —N(C 1-6 alkyl) 2 , —N(C 1-6 alkyl) 3 + X ⁇ , —NH(C 1-6 alkyl) 2 + X ⁇ , —NH 2 (C 1-6 alkyl) + X ⁇ , —NH 3 + X ⁇ , —N(OC 1-6 alkyl)(C 1-6 alkyl), —N(OH)(C 1-6 alkyl), —NH(OH), —SH, —SC 1-6 alkyl, —SS(C 1-6 alkyl), —C( ⁇ O)(C 1-6 alkyl), —CO 2 H, —CO 2 (C 1-6 alkyl), —OC( ⁇ O)
- halo or halogen refers to fluorine (fluoro, —F), chlorine (chloro, —Cl), bromine (bromo, —Br), or iodine (iodo, —I).
- hydroxyl refers to the group —OH.
- substituted hydroxyl or “substituted hydroxyl,” by extension, refers to a hydroxyl group wherein the oxygen atom directly attached to the parent molecule is substituted with a group other than hydrogen, and includes groups selected from —OR aa , —ON(R bb ) 2 , —OC( ⁇ O)SR aa , —OC( ⁇ O)R aa , —OCO 2 R aa , —OC( ⁇ O)N(R bb ) 2 , —OC( ⁇ NR bb )R aa , —OC( ⁇ NR bb )OR aa , —OC( ⁇ NR bb )N(R bb ) 2 , —OS( ⁇ O)R aa , —OSO 2 R aa , —OSi(R aa ) 3 , —
- amino refers to the group —NH 2 .
- substituted amino by extension, refers to a monosubstituted amino, a disubstituted amino, or a trisubstituted amino. In certain embodiments, the “substituted amino” is a monosubstituted amino or a disubstituted amino group.
- the term “monosubstituted amino” refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with one hydrogen and one group other than hydrogen, and includes groups selected from —NH(R bb ), —NHC( ⁇ O)R aa , —NHCO 2 R aa , —NHC( ⁇ O)N(R bb ) 2 , —NHC( ⁇ NR bb )N(R bb ) 2 , —NHSO 2 R aa , —NHP( ⁇ O)(OR cc ) 2 , and —NHP( ⁇ O)(N(R bb ) 2 ) 2 , wherein R aa , R bb and R cc are as defined herein, and wherein R bb of the group —NH(R bb ) is not hydrogen.
- disubstituted amino refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with two groups other than hydrogen, and includes groups selected from —N(R bb ) 2 , —NR bb C( ⁇ O)R aa , —NR bb CO 2 R aa , —NR bb C( ⁇ O)N(R bb ) 2 , —NR bb C( ⁇ NR bb )N(R bb ) 2 , —NR bb SO 2 R aa , —NR bb P( ⁇ O)(OR cc ) 2 , and —NR bb P( ⁇ O)(N(R bb ) 2 ) 2 , wherein R aa , R bb , and R cc are as defined herein, with the proviso that the nitrogen atom directly attached to the parent molecule is not substituted with hydrogen.
- trisubstituted amino refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with three groups, and includes groups selected from —N(R bb ) 3 and —N(R bb ) 3 + X ⁇ , wherein R bb and X ⁇ are as defined herein.
- sulfonyl refers to a group selected from —SO 2 N(R bb ) 2 , —SO 2 R aa , and —SO 2 OR aa , wherein R aa and R bb are as defined herein.
- sulfinyl refers to the group —S( ⁇ O)R aa , wherein R aa is as defined herein.
- acyl refers to a group having the general formula —C( ⁇ O)R X1 , —C( ⁇ O)OR X1 , —C( ⁇ O)—O—C( ⁇ O)R X1 , —C( ⁇ O)SR X1 , —C( ⁇ O)N(R X1 ) 2 , —C( ⁇ S)R X1 , —C( ⁇ S)N(R X1 ) 2 , —C( ⁇ S)O(R X1 ), —C( ⁇ S)S(R X1 ), —C( ⁇ NR X1 )R X1 , —C( ⁇ NR X1 )OR X1 , —C( ⁇ NR X1 )SR X1 , and —C( ⁇ NR X1 )N(R X1 ) 2 , wherein R X1 is hydrogen; halogen; substituted or unsubstituted hydroxyl;
- acyl groups include aldehydes (—CHO), carboxylic acids (—CO 2 H), ketones, acyl halides, esters, amides, imines, carbonates, carbamates, and ureas.
- Acyl substituents include, but are not limited to, any of the substituents described herein, that result in the formation of a stable moiety (e.g., aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, oxo, imino, thiooxo, cyano, isocyano, amino, azido, nitro, hydroxyl, thiol, halo, aliphaticamino, heteroaliphaticamino, alkylamino, heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl, aliphaticoxy, heteroaliphaticoxy, alkyl
- carbonyl refers a group wherein the carbon directly attached to the parent molecule is sp 2 hybridized, and is substituted with an oxygen, nitrogen or sulfur atom, e.g., a group selected from ketones (e.g., —C( ⁇ O)R aa ), carboxylic acids (e.g., —CO 2 H), aldehydes (—CHO), esters (e.g., —CO 2 R aa , —C( ⁇ O)SR aa , —C( ⁇ S)SR aa ), amides (e.g., —C( ⁇ O)N(R bb ) 2 , —C( ⁇ O)NR bb SO 2 R aa , —C( ⁇ S)N(R bb ) 2 ), and imines (e.g., —C( ⁇ NR bb )R aa , —C( ⁇ NR bb )OR aa ), —C( ⁇
- sil refers to the group —Si(R aa ) 3 , wherein R aa is as defined herein.
- oxo refers to the group ⁇ O
- thiooxo refers to the group ⁇ S.
- Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms.
- Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, —OH, —OR aa , —N(R cc ) 2 , —CN, —C( ⁇ O)R aa , —C( ⁇ O)N(R cc ) 2 , —CO 2 R aa , —SO 2 R aa , —C( ⁇ NR bb )R aa —C( ⁇ NR cc )OR aa , —C( ⁇ NR cc )N(R cc ) 2 , —SO 2 N(R cc ) 2 , —SO 2 R cc , —SO 2 OR cc , —SOR aa , —C( ⁇ S)N(R c
- the substituent present on the nitrogen atom is an nitrogen protecting group (also referred to herein as an “amino protecting group”).
- Nitrogen protecting groups include, but are not limited to, —OH, —OR aa , —N(R cc ) 2 , —C( ⁇ O)R aa , —C( ⁇ O)N(R cc ) 2 , —CO 2 R aa , —SO 2 R aa , —C( ⁇ NR cc )R aa , —C( ⁇ NR cc )OR aa , —C( ⁇ NR cc )N(R cc ) 2 , —SO 2 N(R cc ) 2 , —SO 2 R cc , —SO 2 OR cc , —SOR aa , —C( ⁇ S)N(R cc ) 2 , —C( ⁇ O)SR cc , ,
- Nitrogen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis , T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
- nitrogen protecting groups such as amide groups (e.g., —C( ⁇ O)R aa ) include, but are not limited to, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picoiinamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide, p-phenylbenzamide, o-nitophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N′-dithiobenzyloxyacyiamino)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o-mtrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazophenoxylpropanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide,
- Nitrogen protecting groups such as carbamate groups include, but are not limited to, methyl carbamate, ethyl carbamate, 9-fluorenyhnethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethyl
- Nitrogen protecting groups such as sulfonamide groups include, but are not limited to, p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide
- Ts p-toluenesulfonamide
- nitrogen protecting groups include, but are not limited to, phenothiazinyl-(10)-acyl derivative, N′-p-toluenesulfonylaminoacyl derivative, N′-phenylaminothioacyl derivative, N-benzoylphenylalanyl derivative, N-acetylmethionine derivative, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted 3,5-dinitro-4
- a nitrogen protecting group is benzyl (Bn), tert-butyloxycarbonyl (BOC), carbobenzyloxy (Cbz), 9-flurenylmethyloxycarbonyl (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl (Ac), benzoyl (Bz), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), 2,2,2-trichloroethyloxycarbonyl (Troc), triphenylmethyl (Tr), tosyl (Ts), brosyl (Bs), nosyl (Ns), mesyl (Ms), triflyl (Tf), or dansyl (Ds).
- Bn benzyl
- BOC tert-butyloxycarbonyl
- Cbz carbobenzyloxy
- Fmoc 9-flurenylmethyloxycarbony
- the substituent present on an oxygen atom is an oxygen protecting group (also referred to herein as an “hydroxyl protecting group”).
- Oxygen protecting groups include, but are not limited to, —R aa , —N(R bb ) 2 , —C( ⁇ O)SR aa , —C( ⁇ O)R aa , —CO 2 R aa , —C( ⁇ O)N(R bb ) 2 , —C( ⁇ NR bb )R aa , —C( ⁇ NR bb )OR aa , —C( ⁇ NR bb )N(R bb ) 2 , —S( ⁇ O)R aa , —SO 2 R aa , —Si(R aa ) 3 , —P(R cc ) 2 , —P(R cc ) 3 + X ⁇ , —P(OR cc
- Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
- oxygen protecting groups include, but are not limited to, methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacohnethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethyisilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl (
- an oxygen protecting group is silyl.
- an oxygen protecting group is t-butyldiphenylsilyl (TBDPS), t-butyldimethylsilyl (TBDMS), triisopropylsilyl (TIPS), triphenylsilyl (TPS), triethylsilyl (TES), trimethylsilyl (TMS), triisopropylsiloxymethyl (TOM), acetyl (Ac), benzoyl (Bz), allyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-trimethylsilylethyl carbonate, methoxymethyl (MOM), 1-ethoxyethyl (EE), 2-methyoxy-2-propyl (MOP), 2,2,2-trichloroethoxyethyl, 2-methoxyethoxymethyl (MEM), 2-trimethylsilylethoxymethyl (SEM), methylthiomethyl (MTM), tetra
- the substituent present on a sulfur atom is a sulfur protecting group (also referred to as a “thiol protecting group”).
- Sulfur protecting groups include, but are not limited to, —R aa , —N(R bb ) 2 , —C( ⁇ O)SR aa , —C( ⁇ O)R aa , —CO 2 R aa , —C( ⁇ O)N(R bb ) 2 , —C( ⁇ NR bb )R aa , —C( ⁇ NR bb )OR aa , —C( ⁇ NR bb )N(R bb ) 2 , —S( ⁇ O)R aa , —SO 2 R aa , —Si(R aa ) 3 , —P(R cc ) 2 , —P(R cc ) 3 + X ⁇ , —P(OR c
- a sulfur protecting group is acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl.
- a “counterion” or “anionic counterion” is a negatively charged group associated with a positively charged group in order to maintain electronic neutrality.
- An anionic counterion may be monovalent (i.e., including one formal negative charge).
- An anionic counterion may also be multivalent (i.e., including more than one formal negative charge), such as divalent or trivalent.
- Exemplary counterions include halide ions (e.g., F ⁇ , Cl ⁇ , Br ⁇ , I ⁇ ), NO 3 ⁇ , ClO 4 ⁇ , OH ⁇ , H 2 PO 4 ⁇ , HCO 3 ⁇ HSO 4 ⁇ , sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphor sulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate, ethan-1-sulfonic acid-2-sulfonate, and the like), carboxylate ions (e.g., acetate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate, and the like), BF 4 ⁇
- Exemplary counterions which may be multivalent include CO 3 2 ⁇ , HPO 4 2 ⁇ , PO 4 ⁇ , B 4 O 7 2 ⁇ , SO 4 2 ⁇ , S 2 O 3 2 ⁇ , carboxylate anions (e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like), and carboranes.
- carboxylate anions e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like
- carboranes e.g., tartrate, citrate, fumarate, maleate, mal
- leaving group is given its ordinary meaning in the art of synthetic organic chemistry and refers to an atom or a group capable of being displaced by a nucleophile. See, for example, Smith, March's Advanced Organic Chemistry 6th ed. (501-502).
- Suitable leaving groups include, but are not limited to, halogen (such as F, Cl, Br, or I (iodine)), alkoxycarbonyloxy, aryloxycarbonyloxy, alkanesulfonyloxy, arenesulfonyloxy, alkyl-carbonyloxy (e.g., acetoxy), arylcarbonyloxy, aryloxy, methoxy, N,O-dimethylhydroxylamino, pixyl, and haloformates.
- halogen such as F, Cl, Br, or I (iodine
- the leaving group is a sulfonic acid ester, such as toluenesulfonate (tosylate, —OTs), methanesulfonate (mesylate, —OMs), p-bromobenzenesulfonyloxy (brosylate, —OBs), —OS( ⁇ O) 2 (CF 2 ) 3 CF 3 (nonaflate, —ONf), or trifhioromethanesulfonate (triflate, —OTf).
- the leaving group is a brosylate, such as p-bromobenzenesulfonyloxy.
- the leaving group is a nosylate, such as 2-nitrobenzenesulfonyloxy.
- the leaving group may also be a phosphineoxide (e.g., formed during a Mitsunobu reaction) or an internal leaving group such as an epoxide or cyclic sulfate.
- phosphineoxide e.g., formed during a Mitsunobu reaction
- an internal leaving group such as an epoxide or cyclic sulfate.
- Other non-limiting examples of leaving groups are water, ammonia, alcohols, ether moieties, thioether moieties, zinc halides, magnesium moieties, diazonium salts, and copper moieties.
- Further exemplary leaving groups include, but are not limited to, halo (e.g., chloro, bromo, iodo) and activated substituted hydroxyl groups (e.g., —OC( ⁇ O)SR aa , —OC( ⁇ O)R aa , —OCO 2 R aa , —OC( ⁇ O)N(R bb ) 2 , —OC( ⁇ NR bb )R aa , —OC( ⁇ NR bb )OR aa , —OC( ⁇ NR bb )N(R bb ) 2 , —OS( ⁇ O)R aa , —OSO 2 R aa , —OP(R cc ) 2 , —OP(R cc ) 3 , —OP( ⁇ O) 2 R aa , —OP( ⁇ O)(R aa ) 2 , —OP( ⁇ O)(OR cc
- At least one instance refers to 1, 2, 3, 4, or more instances, but also encompasses a range, e.g., for example, from 1 to 4, from 1 to 3, from 1 to 2, from 2 to 4, from 2 to 3, or from 3 to 4 instances, inclusive.
- non-hydrogen group refers to any group that is defined for a particular variable that is not hydrogen.
- amplify and “amplification” as used herein means amplification of reporter signal.
- the term “deposition” means directed binding of a reactive intermediate to the receptor which results from the formation of a covalent bond.
- reactive intermediate means the substrate portion of the conjugate has been primed by the enzyme to bind to the receptor.
- the phenolic moiety is converted to the reactive intermediate, which can bind to the receptor.
- salt refers to any and all salts, and encompasses pharmaceutically acceptable salts.
- pharmaceutically acceptable salt refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio.
- Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference.
- Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases.
- Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange.
- inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid
- organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange.
- salts include adipate, alginate-ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate
- Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N + (C 1-4 alkyl) 4 ⁇ salts.
- Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
- Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.
- solvate refers to forms of the compound, or a salt thereof, that are associated with a solvent, usually by a solvolysis reaction. This physical association may include hydrogen bonding.
- Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like.
- the compounds described herein may be prepared, e.g., in crystalline form, and may be solvated.
- Suitable solvates include pharmaceutically acceptable solvates and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of a crystalline solid.
- “Solvate” encompasses both solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates, and methanolates.
- hydrate refers to a compound that is associated with water.
- the number of the water molecules contained in a hydrate of a compound is in a definite ratio to the number of the compound molecules in the hydrate. Therefore, a hydrate of a compound may be represented, for example, by the general formula R ⁇ x H 2 O, wherein R is the compound, and x is a number greater than 0.
- a given compound may form more than one type of hydrate, including, e.g., monohydrates (x is 1), lower hydrates (x is a number greater than 0 and smaller than 1, e.g., hemihydrates (R ⁇ 0.5 H 2 O)), and polyhydrates (x is a number greater than 1, e.g., dihydrates (R ⁇ 2 H 2 O) and hexahydrates (R ⁇ 6 H 2 O)).
- monohydrates x is 1
- lower hydrates x is a number greater than 0 and smaller than 1, e.g., hemihydrates (R ⁇ 0.5 H 2 O)
- polyhydrates x is a number greater than 1, e.g., dihydrates (R ⁇ 2 H 2 O) and hexahydrates (R ⁇ 6 H 2 O)
- tautomers or “tautomeric” refers to two or more interconvertible compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valency (e.g., a single bond to a double bond, a triple bond to a single bond, or vice versa).
- the exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Tautomerizations (i.e., the reaction providing a tautomeric pair) may catalyzed by acid or base.
- Exemplary tautomerizations include keto-to-enol, amide-to-imide, lactam-to-lactim, enamine-to-imine, and enamine-to-(a different enamine) tautomerizations.
- stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”.
- enantiomers When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible.
- An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or ( ⁇ )-isomers respectively).
- a chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.
- polymorph refers to a crystalline form of a compound (or a salt, hydrate, or solvate thereof). All polymorphs have the same elemental composition. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form to dominate. Various polymorphs of a compound can be prepared by crystallization under different conditions.
- tissue sample refers to any sample including tissue samples (such as tissue sections and needle biopsies of a tissue); cell samples (e.g., cytological smears (such as Pap or blood smears) or samples of cells obtained by microdissection); samples of whole organisms (such as samples of yeasts or bacteria); or cell fractions, fragments or organelles (such as obtained by lysing cells and separating the components thereof by centrifugation or otherwise).
- tissue samples such as tissue sections and needle biopsies of a tissue
- cell samples e.g., cytological smears (such as Pap or blood smears) or samples of cells obtained by microdissection) or samples of cells obtained by microdissection
- samples of whole organisms such as samples of yeasts or bacteria
- cell fractions, fragments or organelles such as obtained by lysing cells and separating the components thereof by centrifugation or otherwise.
- biological samples include blood, serum, urine, semen, fecal matter, cerebrospinal fluid, interstitial fluid, mucous, tears, sweat, pus, biopsied tissue (e.g., obtained by a surgical biopsy or needle biopsy), nipple aspirates, milk, vaginal fluid, saliva, swabs (such as buccal swabs), or any material containing biomolecules that is derived from a first biological sample.
- tissue refers to any biological tissue of a subject (including a group of cells, a body part, or an organ) or a part thereof, including blood and/or lymph vessels, which is the object to which a compound, particle, and/or composition of the invention is delivered.
- a tissue may be an abnormal or unhealthy tissue, which may need to be treated.
- a tissue may also be a normal or healthy tissue that is under a higher than normal risk of becoming abnormal or unhealthy, which may need to be prevented.
- the tissue is the central nervous system.
- the tissue is the brain.
- the disclosure provides compounds of Formula (I), and salts, chelate complexes, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and compositions thereof.
- the disclosure provides chelate complexes comprising the compounds of Formula (I) and a metal cation.
- the compounds described herein possess hydrogen donating moieties that can be oxidized when contacted with an enzyme activation system (e.g., a peroxidase).
- an enzyme activation system e.g., a peroxidase
- the oxidized compound is useful in methods of catalyzed reporter deposition for the detection of analytes in biological samples.
- the macrocyclic DOTA moiety functions as a reporter group which can be detected by a variety of detection methods (e.g., mass spectrometry based imaging).
- the compounds are particularly useful in the methods and uses described herein when the DOTA moiety comprises a chelate complex having a metal counterion (e.g., lanthanides, yttrium, praesodynium).
- the DOTA-containing compounds and complexes are advantageous over existing reporter compounds and complexes because the DOTA moiety allows detection of the reporter moiety by use of mass spectrometry imaging microscopy.
- a compound may be provided for use in any composition, kit, or method described herein as a salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or chelate complex thereof.
- G is a chelating moiety
- R 1 is substituted or unsubstituted alkylene, a bond, —O—, —S—, or —NR A —;
- R 2 is a bond, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
- X 1 is a bond or N
- X is O or S
- R 5 is hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, or a nitrogen protecting group
- R 4 is substituted or unsubstituted C 2 -C 6 heteroaliphatic, substituted or unsubstituted C 2 -C 6 alkylene, substituted or unsubstituted C 2 -C 6 alkenylene, or substituted or unsubstituted C 2 -C 6 alkynylene;
- R 5 is hydrogen, halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —N(R A ) 2 , or —OR A ;
- R 6 is hydrogen, halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —N(R A ) 2 , or —OR A ;
- R 7 is hydrogen, halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —N(R A ) 2 , or —OR A ;
- R 8 is hydrogen, halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —N(R A ) 2 , or —OR A ; and
- each occurrence of R A is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, a nitrogen protecting group when attached to a nitrogen atom, or an oxygen protecting group when attached to a nitrogen atom, or two R A groups are joined to form a substituted or unsubstituted heterocyclic ring.
- Chelation is a type of bonding of ions and molecules to metal ions. It involves the formation or presence of coordinate bonds between a ligand and a single central atom.
- the ligand may be polydentate, or multiply bonded.
- these ligands are organic compounds, and are called chelants, chelators, chelating agents, or sequestering agents.
- G is a chelating moiety.
- G comprises amino acid moieties that act as chelating atoms.
- G is a heterocyclic moiety.
- G is an acyclic moiety.
- G is capable of forming a chelate complex with a metal ion.
- G is of the formula
- G is of the formula
- R 1 is substituted or unsubstituted alkylene, a bond, —O—, —S—, or —NR A —.
- R 1 is substituted or unsubstituted alkylene.
- R 1 is substituted or unsubstituted C 1 -C 6 alkylene.
- R 1 is unsubstituted C 1 -C 6 alkylene.
- R 1 is unsubstituted C 1 -C 5 alkylene.
- R 1 is unsubstituted C 1 -C 4 alkylene.
- R 1 is unsubstituted C 1 -C 3 alkylene.
- R 1 is unsubstituted C 1 -C 2 alkylene. In certain embodiments, R 1 is methylene. In certain embodiments, R 1 is ethylene. In certain embodiments, R 1 is propylene. In certain embodiments, R 1 is butylene. In certain embodiments, R 1 is pentylene. In certain embodiments, R 1 is hexylene.
- R 2 is a bond, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.
- R 2 is substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.
- R 2 is substituted or unsubstituted carbocyclylene.
- R 2 is substituted or unsubstituted heterocyclylene.
- R 2 is substituted or unsubstituted arylene or substituted or unsubstituted heteroarylene. In certain embodiments, R 2 is substituted or unsubstituted arylene. In certain embodiments, R 2 is unsubstituted arylene. In certain embodiments, R 2 is substituted or unsubstituted phenylene. In certain embodiments, R 2 is unsubstituted phenylene.
- R 1 is substituted or unsubstituted C 1 -C 6 alkylene and R 2 is substituted or unsubstituted phenylene. In certain embodiments, R 1 is unsubstituted C 1 -C 6 alkylene and R 2 is unsubstituted phenylene.
- X is O or S. In certain embodiments, X is O. In certain embodiments, X is S.
- R 1 is substituted or unsubstituted G-G alkylene; R 2 is substituted or unsubstituted phenylene; and X is O. In certain embodiments, R 1 is unsubstituted C 1 -C 6 alkylene; R 2 is unsubstituted phenylene; and X is O.
- R 1 is substituted or unsubstituted C 1 -C 6 alkylene; R 2 is substituted or unsubstituted phenylene; and X is S. In certain embodiments, R 1 is unsubstituted C 1 -C 6 alkylene; R 2 is unsubstituted phenylene; and X is S.
- X 1 is a bond or N. In certain embodiments, X 1 is A bond. In certain embodiments, X 1 is N.
- R 3 is hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, or a nitrogen protecting group. In certain embodiments, R 3 is substituted or unsubstituted C 1 -C 6 alkyl. In certain embodiments, R 3 is unsubstituted C 1 -C 6 alkyl. In certain embodiments, R 3 is unsubstituted C 1 -C 2 alkyl. In certain embodiments, R 3 is unsubstituted C 1 -C 4 alkyl. In certain embodiments, R 2 is unsubstituted C 1 -C 3 alkyl. In certain embodiments, R 3 is unsubstituted C 1 -C 2 alkyl.
- R 3 is methyl. In certain embodiments, R 3 is ethyl. In certain embodiments, R 3 is propyl. In certain embodiments, R 3 is butyl. In certain embodiments, R 3 is pentyl. In certain embodiments, R 3 is hexyl. In certain embodiments, R 3 is a nitrogen protecting group. In certain embodiments, R 3 is hydrogen.
- R 1 is substituted or unsubstituted C 1 -C 6 alkylene; R 2 is substituted or unsubstituted phenylene; and X is O. In certain embodiments, R 1 is unsubstituted C 1 -C 6 , alkylene; R 2 is unsubstituted phenylene; X is O; and R 2 is hydrogen.
- R 1 is substituted or unsubstituted C 1 -C 6 alkylene; R 2 is substituted or unsubstituted phenylene; and X is S. In certain embodiments, R 1 is unsubstituted C 1 -C 6 alkylene; R 2 is unsubstituted phenylene; X is S; and R 3 is hydrogen.
- R 4 is substituted or unsubstituted C 2 -C 6 heteroaliphatic, substituted or unsubstituted C 2 -C 6 alkylene, substituted or unsubstituted C 1 -C 6 alkenylene, or substituted or unsubstituted C 2 -C 6 alkynylene.
- R 4 is substituted or unsubstituted C 2 -C 6 heteroaliphatic, substituted or unsubstituted C 1 -C 6 alkylene, or substituted or unsubstituted C 2 -C 6 alkenylene.
- R 4 is unsubstituted C 2 -C 6 heteroaliphatic, unsubstituted C 2 -C 6 alkylene, or unsubstituted C 2 -C 6 alkenylene. In certain embodiments, R 4 is unsubstituted C 2 -C 6 heteroalkylene, unsubstituted C 2 -C 0 alkylene, or unsubstituted C 2 -C 6 alkenylene.
- R 4 is unsubstituted C 2 -C 6 alkylene. In certain embodiments, R 4 is unsubstituted C 2 -C 5 alkylene. In certain embodiments, R 4 is unsubstituted C 2 -C 4 alkylene. In certain embodiments, R 4 is unsubstituted C 2 -C 3 alkylene. In certain embodiments, R 4 is unsubstituted ethylene.
- R 4 is unsubstituted C 2 -G, alkenylene. In certain embodiments, R 4 is unsubstituted C 2 -C 5 alkenylene. In certain embodiments, R 4 is unsubstituted C 2 -C 4 alkenylene. In certain embodiments, R 4 is unsubstituted C 2 -C 3 alkenylene. In certain embodiments, R 4 is unsubstituted ethenylene.
- R 4 is substituted or unsubstituted C 2 -C 6 heteroalkylene. In certain embodiments, R 4 is unsubstituted C 2 -C 6 heteroalkylene. In certain embodiments, R 4 is unsubstituted C 2 -C 5 heteroalkylene. In certain embodiments, R 4 is unsubstituted C 2 -C 4 heteroalkylene. In certain embodiments, R 4 is unsubstituted C 2 -C 3 heteroalkylene. In certain embodiments, R 4 is unsubstituted C 2 heteroalkylene. In certain embodiments, R 4 is of the formula
- R 4 is
- R 4 is
- R 5 , R 6 , R 7 , and R 8 are each independently hydrogen, halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —N(R A ) 2 , or —OR A .
- R 5 , R 6 , R 7 , and R 8 are independently hydrogen, halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyl, —N(R A ) 2 , or —OR A .
- R 5 , R 6 , R 7 , and R 8 are independently hydrogen, halogen, nitro, cyano, unsubstituted alkyl, unsubstituted alkenyl, —N(R A ) 2 , or —OR A .
- R 5 , R 6 , R 7 , and R 8 are independently hydrogen, halogen, nitro, cyano, unsubstituted C 1 -C 6 alkyl, unsubstituted C 2 -C 4 alkenyl, —N(R A ) 2 , or —OR A .
- R 5 , R 6 , R 7 , and R 8 are independently hydrogen, —N(R A ) 2 , or —OR A In certain embodiments, R 5 , R 6 , R 7 , and R 8 are independently hydrogen, —N(R A ) 2 , or —OR A ; and each R A is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, a nitrogen protecting group, or an oxygen protecting group.
- R 5 , R 6 , R 7 , and R 8 are independently hydrogen, —N(R A ) 2 , or —OR A ; and each R A is independently hydrogen, substituted or unsubstituted acyl, a nitrogen protecting group, or an oxygen protecting group.
- R 5 , R 6 , R 7 , and R 8 are independently hydrogen, —N(R A ) 2 , or —OR A ; and each R A is independently hydrogen, a nitrogen protecting group, or an oxygen protecting group.
- R 5 , R 6 , R 7 , and R 8 are independently hydrogen, —N(R A ) 2 , or —OR A ; and each R A is hydrogen.
- R 5 , R 6 , R 7 , and R 8 are independently hydrogen or —OR A ; and R A is hydrogen.
- At least one of R 5 , R 6 , R 7 , and R 8 is —OR A . In certain embodiments, at least one of R 5 , R 6 , R 7 , and R 8 is —OH. In certain embodiments, two of R 5 , R 6 , R 7 , and R 8 are —OR A . In certain embodiments, two of R 5 , R 6 , R 7 , and R 8 are —OH. In certain embodiments, R 5 and R 8 are hydrogen; and R 6 and R 7 are independently hydrogen or —OR A . In certain embodiments, R 5 , R 7 , and R 8 are each hydrogen.
- R 5 , R 7 , and R 8 are each hydrogen; and R 6 is hydrogen or —OR A . In certain embodiments, R 5 , R 7 , and R 8 are each hydrogen; and R 6 is hydrogen or —OH. In certain embodiments, R 5 , R 6 , R 7 , and R 8 are each hydrogen.
- the compound of Formula (I) is a compound of Formula (I-a):
- R 1 , R 2 , R 3 , X, R 4 , R 5 , R 6 , R 7 , R 8 , and R A are as defined herein.
- the compound of Formula (I) is a compound of Formula (I-b):
- R 1 , R 2 , R 3 , X, R 4 , R 5 , R 6 , R 7 , R 8 , and R A are as defined herein.
- the compound of Formula (I) is a compound of Formula (I-c):
- R 3 , X, R 4 , R 5 , R 6 , R 7 , R 8 , and R A are as defined herein.
- the compound of Formula (I) is a compound of Formula (I-d):
- R 4 , R 5 , R 6 , R 7 , R 8 , and R A are as defined herein.
- the compound of Formula (I) is a compound of Formula (I-e):
- R 5 , R 6 , R 7 , R 8 , and R A are as defined herein.
- the compound of Formula (I) is a compound of Formula (I-f):
- R 6 and R A are as defined herein.
- the compound of Formula (I) is a compound of Formula (I-g):
- R 1 , R 2 , and R 3 are as defined herein.
- the compound of Formula (I) is a compound of Formula (I-h):
- R 5 , R 6 , R 7 , R 8 , and R A are as defined herein.
- the compound of Formula (I) is a compound of Formula (I-i):
- R 6 and R A are as defined herein.
- the compound of Formula (I) is a compound of Formula
- R 1 , R 2 , and R 3 are as defined herein.
- the compound of Formula (I) is a compound of Formula (I-k):
- R 4 , R 5 , R 6 , R 7 , R 8 , and R A are as defined herein.
- the compound of Formula (I) is a compound of Formula (I-l):
- R 5 , R 6 , R 7 , R 8 , and R A are as defined herein.
- the compound of Formula (I) is a compound of Formula (I-m):
- R 6 and R A are as defined herein.
- the compound of Formula (I) is a compound of Formula (I-n):
- R 1 , R 2 , and R 3 are as defined herein.
- the compound of Formula I is a compound of Table 1, or a salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or chelate complex thereof.
- the salt comprises a metal counterion
- the metal counterion is bismuth, lead, yttrium, cadmium, mercury, actinium, thorium, strontium, or a lanthanide.
- the metal counterion has an oxidation state of +3.
- the metal counterion is yttrium, praseodymium, or lutetium.
- the metal counterion is yttrium.
- the metal counterion is Y 3+ .
- the metal counterion is praseodymium.
- the metal counterion is P 3+ .
- chelate complexes comprising the compound of Formula (I) or a salt thereof.
- a chelate complex is a chemical compound composed of a metal ion and a chelating agent.
- a chelating agent forms one or more bonds to a single metal ion.
- the compound of Formula (I) may be a chelating agent.
- the chelate complex comprising a compound of Formula (I), or a salt thereof is a monovalent chelate complex.
- the chelate complex comprising a compound of Formula (I), or a salt thereof is a divalent chelate complex.
- the chelate complex comprising a compound of Formula (I), or a salt thereof is a trivalent chelate complex.
- the metal ion is bismuth, lead, yttrium, cadmium, mercury, actinium, thorium, strontium, or a lanthanide, hi certain embodiments, the metal ion is yttrium, praseodymium, or lutetium. In certain embodiments, the metal ion has an oxidation state of +3. In certain embodiments, the metal ion is yttrium. In certain embodiments, the metal ion is Y 3+ . In certain embodiments, the metal ion is praseodymium. In certain embodiments, the metal ion is P 3+ .
- the chelate complex comprising the compound of Formula (I), or a salt thereof is any of the formula of Table 2.
- kits may comprise a compound, salt, or chelate complex described herein and a container (e.g., a vial, ampule, bottle, syringe, and/or dispenser package, or other suitable container).
- the kit further comprises an activating enzyme.
- the enzyme is a peroxidase.
- the enzyme is horseradish peroxidase.
- kits including a container comprising a compound, salt, or chelate complex described herein.
- the kits are useful for assaying methods to detect an analyte (e.g., a protein from human tissue, nucleic acids).
- an analyte e.g., a protein from human tissue, nucleic acids.
- a kit described herein further includes instructions for using the kit.
- DOTA-containing compounds e.g., compounds of Formula (I)
- complexes that are reactive with an enzyme activator (e.g., a peroxidase) and covalently bind a target analyte (e.g., a protein, nucleic acids) in a catalyzed reporter deposition assaying method.
- the macrocyclic DOTA portion of the molecule may then act as a reporter group which can be detected directly (e.g., mass spectrometry based imaging) or indirectly (e.g., DOTA antibody coupled to chromogenic deposition of a light-emitting compound and visualization with light or fluorescence microscopy).
- the compounds are most useful in the methods and uses described herein when they comprise a chelate complex having a metal counterion (e.g., lanthanides, yttrium, praesodynium).
- a metal counterion e.g., lanthanides, yttrium, praesodynium.
- the DOTA-containing compounds and complexes are advantageous over existing reporter compounds and complexes because the DOTA moiety allows detection of the reporter moiety by use of mass spectrometry imaging microscopy.
- a method of detecting an analyte comprising: reacting an enzyme with a chelate complex (e.g., comprising a compound of Formula (I)) described herein to form an oxidized chelate complex; contacting the oxidized chelate complex with a biological sample; and detecting the analyte in the biological sample.
- a chelate complex e.g., comprising a compound of Formula (I)
- the method further comprises covalent binding of the oxidized chelate complex with the analyte.
- the biological sample is immobilized.
- the analyte comprises a protein derived from human tissue.
- the enzyme is a peroxidase. In certain embodiments, the enzyme is horseradish peroxidase. In certain embodiments, the analyte does not react with the enzyme.
- the detecting of the analyte is direct or indirect. In certain embodiments, the detecting of the analyte is indirect. In certain embodiments, the detecting of the analyte comprises adding a DOTA chelate-specific antibody coupled to chromogenic deposition of a light-emitting compound (e.g., 3,3′-diaminobenzidine tetrahydrochloride) and visualization with light or fluorescence microscopy.
- a light-emitting compound e.g., 3,3′-diaminobenzidine tetrahydrochloride
- the detecting of the analyte is direct. In certain embodiments, the detecting of the analyte comprises mass spectrometry imaging based microscopy. In certain embodiments, the detecting is achieved by employing mass spectrometry imaging based microscopy. In certain embodiments, the detecting is achieved by employing multiplexed ion beam imaging (MIBI). In certain embodiments, the detecting is achieved by employing Imaging Mass CytometryTM (IMCTM).
- MIBI multiplexed ion beam imaging
- IMCTM Imaging Mass CytometryTM
- Compound 1 was prepared by the following synthetic scheme.
- Compound 2 was prepared by the following synthetic scheme.
- Compound 3 was prepared by the following synthetic scheme.
- Table A (anti-nestin positive control) provides the assay procedure for demonstrating the expression of the intermediate filament protein nestin detected in normal human kidney podocytes using a goat anti-nestin polyclonal antibody with a rabbit anti-goat secondary horseradish peroxidase/3,3′-diaminobenzidine (DAB) chromogenic assay and standard light microscopy ( FIG. 1A ).
- DAB horseradish peroxidase/3,3′-diaminobenzidine
- Tables B and C provide the assay procedures for demonstrating that the chromogenic signal for nestin expression is not seen with negative control conditions including without anti-nestin primary antibody (Table C; FIG. 1C ) or without secondary antibody (Table B; FIG. 1B ).
- Table D provides the assay procedure for demonstrating that the nestin-specific signal is not seen without the DOTA chelate complex in the anti-DOTA antibody assay ( FIG. 1D ).
- Table E provides the assay procedure for evaluating exemplary compounds 1, 2, and 3 having DOTA complexed to Pr 3+ ( FIG. 1E , FIG. 1I , FIG. 1M ) or Y 3+ ( FIG. 1F , FIG. 1J , FIG. 1N ) or not complexed ( FIG. 1G , FIG. 1K , FIG. 1O ).
- the complex was oxidized by peroxidase and deposited at the site of the anti-nestin antibody. This specific deposition of complex was detected with an anti-DOTA chelate antibody (clone 2D12.5) chromogenic assay using DAB. Empty DOTA is not recognized by the anti-DOTA chelate antibody (clone 2D12.5), therefore chromogenic signal was not seen in these assay conditions ( FIG. 1G , FIG. 1K , FIG. 1O ).
- Table F provides the assay procedure for evaluating exemplary compounds 1, 2, and 3 having DOTA complexed to Y 3+ ( FIG. 1H , FIG. 1L , FIG. 1P ) but without addition of the anti-DOTA antibody to the assay. Nestin-specific signal was not seen without anti-DOTA chelate antibody ( FIG. 1H , FIG. 1L , FIG. 1P ).
- FIG. 2 confirms that the disclosed compounds can be detected by a mass spectrometry imaging device in an assay. Images were generated using a MIBIscope I multiplexed ion beam imaging device from IONpath (Menlo Park, Calif.). The parenthetical terms 1:4K, 1:2K, and 1:1K refer to the dilution of the compound used in the assay. In particular, compounds 1 and 3 complexed to Pr 3+ ( FIGS. 2A, 2C ) or Y 3+ ( FIGS. 2B, 2D ) were detected directly in human placenta samples using the mass spectrometry imaging device.
- Step Reagent Inc. Temperature: Supplier Santo Cruze 1 Goat anti- 30:00 Ambient Cat# SC-21248; human Lot# A2313 NESTIN Dispense type: 150 ⁇ L Step type: Reagent Step Reagent Inc. (min): Temperature: Supplier: Leica 2 *BondWashSolution 0:00 Ambient Microsystems Step type: Wash Dispense type. 150 ⁇ L Step Reagent Inc. (min): Temperature: Supplier: Leica 3 *BondWashSolution 0:00 Ambient Microsystems Step type: Wash Dispense type. 150 ⁇ L Step Reagent Inc.
- Step Reagent Inc. 30:00 Temperature: Ambient Supplier: VWR 1 TBS-t Cat# J640-1L Step type: Reagent Dispense type: 150 ⁇ L Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: Leica Microsystems 2 *BondWashSolution Dispense type: 150 ⁇ L Step type: Wash Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: Leica Microsystems 3 *BondWashSolution Dispense type: 150 ⁇ L Step type: Wash Step Reagent Inc.
- Step Reagent Inc. 30:00 Temperature: Ambient Supplier: SantaCruze, (Cat# SC-21248; 1 Goat anti- Lot# A2313) human Dispense type: 150 ⁇ L NESTIN Step type: Reagent Step Reagent Inc. (min): 2:00 Temperature: Ambient Supplier: Leica Microsystems 2 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 ⁇ L Step Reagent Inc. (min): 2:00 Temperature: Ambient Supplier: Leica Microsystems 3 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 ⁇ L Step Reagent Inc.
- Reagent Dispense type 150 ⁇ L Step Reagent Inc. (min): 0:00 Temperature: 100 Supplier: Perkin Elmer 23 AR9 Buffer Cat# AR900250ML Step type: Reagent Dispense type: 150 ⁇ L Step Reagent Inc. (min): 2:00 Temperature: Ambient Supplier: Perkin Elmer 24 AR9 Buffer Cat#AR900250ML Step type: Reagent Dispense type: 150 ⁇ L Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: Perkin Elmer 25 AR9 Buffer Cat# AR900250ML Step type: Reagent Dispense type: 150 ⁇ L Step Reagent Inc.
- the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim.
- any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim.
- elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the invention, or aspects of the invention, is/are referred to as comprising particular elements and/or features, certain embodiments of the invention or aspects of the invention consist, or consist essentially of, such elements and/or features.
Abstract
Description
- The present application claims priority under 35 U.S.C. § 119(e) to U.S. provisional application U.S. Ser. No. 62/684,573, filed Jun. 13, 2018, which is incorporated herein by reference.
- Catalyzed reporter deposition (CARD) is a method of signal amplification useful in assaying biological samples for analyte detection. See U.S. Pat. Nos. 5,731,158, 5,583,001, and 5,196,306 which are hereby incorporated by reference. The CARD method utilizes an analyte-dependent enzyme activation system (ADEAS) to catalyze the deposition of reporter groups (e.g., fluorescein, biotin) onto a receptor, the receptor being part of or added to a surface in contact with the components of the assay. These enzymatically deposited labels are detected directly or indirectly, resulting in signal amplification and improved detection limits. Peroxidases, such as horseradish peroxidase (HRP) are the preferred enzymes for the method.
- In the method, the peroxidase oxidizes a hydrogen-donating moiety of a substrate conjugate comprising a labeled compound. When the enzyme and the substrate react, a reactive intermediate is formed, which binds covalently with electron-rich residues near the receptor of the reactive intermediate. Hydrogen-donating moieties that are reactive with peroxidase enzymes include substituted phenols, such as tyramides, tyramines, and p-hydroxycinnamoyl-containing compounds. Specific reporters attached to the conjugate can be detected by fluorescence or light microscopy at the specific site of covalent attachment.
- An ongoing need exists to identify molecules useful in the CARD method that can effectively bind specific target analytes to improve analyte detection.
- The
macrocycle 1,4,7,10-tetraazacyclododecane-1,4,7-tetraacetic acid (DOTA) is a chelating agent that can be employed in constructing compounds useful in the CARD method of detecting analytes in biological samples. In particular, the chelated form of DOTA can serve as a reporter moiety and be linked to reactive molecules (e.g., phenols) to form a compound that can bind to specific biological target molecules for analyte detection. The present disclosure describes DOTA-tyramide, DOTA-tyramine, and DOTA-cinnamamide compounds, salts, and chelate complexes thereof that are useful for site-specific binding and analyte detection. The DOTA containing compounds offer advantages over existing reporter compounds because the DOTA moiety can be detected directly (e.g., by mass spectrometry based imaging microscopy). - In one aspect, provided are compounds of Formula (I):
- and salts thereof, wherein:
- G is a chelating moiety;
- R1 is substituted or unsubstituted alkylene, a bond, —O—, —S—, or —NRA—;
- R2 is a bond, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
- X1 is a bond or N;
- X is O or S;
- R3 is hydrogen, substituted or unsubstituted C1-C6 alkyl, or a nitrogen protecting group;
- R4 is substituted or unsubstituted C2-C6 heteroaliphatic, substituted or unsubstituted C2-C6 alkylene, substituted or unsubstituted C2-C6 alkenylene, or substituted or unsubstituted C2-C6 alkynylene;
- R5 is hydrogen, halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —N(RA)2, or —ORA;
- R6 is hydrogen, halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —N(RA)2, or —ORA;
- R7 is hydrogen, halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —N(RA)2, or —ORA;
- R8 is hydrogen, halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —N(RA)2, or —ORA; and each occurrence of RA is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, a nitrogen protecting group when attached to a nitrogen atom, or an oxygen protecting group when attached to an oxygen atom, or two RA groups are joined to form a substituted or unsubstituted heterocyclic ring.
- In certain embodiments, the compound of Formula (I) is a compound of Formula (I-a):
- and salts thereof, wherein:
- R1 is substituted or unsubstituted alkylene, a bond, —O—, —S—, or —NRA;
- R2 is substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
- X is O or S;
- R3 is hydrogen, substituted or unsubstituted C1-C6 alkyl, or a nitrogen protecting group;
- R4 is substituted or unsubstituted C2-C6 heteroaliphatic, substituted or unsubstituted C2-C6 alkylene, substituted or unsubstituted C2-C6 alkenylene, or substituted or unsubstituted C2-C6 alkynylene;
- R5 is hydrogen, halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —N(RA)2, or —ORA;
- R6 is hydrogen, halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —N(RA)2, or —ORA;
- R7 is hydrogen, halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —N(RA)2, or —ORA;
- R8 is hydrogen, halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —N(RA)2, or —ORA; and
- each occurrence of RA is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, a nitrogen protecting group when attached to a nitrogen atom, or an oxygen protecting group when attached to an oxygen atom, or two RA groups are joined to form a substituted or unsubstituted heterocyclic ring.
- Exemplary compounds of Formula (I) include, but are not limited to:
- and salts thereof.
- In another aspect, provided are salts comprising a compound of Formula (I). In certain embodiments, the salt comprises a metal counterion (e.g., bismuth, lead, yttrium, cadmium, mercury, actinium, thorium, strontium, or a lanthanide). In certain embodiments, the metal counterion is yttrium, praseodymium, or lutetium.
- In another aspect, provided are chelate complexes comprising a compound of Formula (I), or a salt of a compound of Formula (I). In certain embodiments, the chelate complex is a trivalent complex.
- Exemplary chelate complexes comprising compounds of Formula (I) include, but are not limited to:
- In another aspect, provided are methods of detecting an analyte, the method comprising reacting an enzyme (e.g., a peroxidase) with a chelate complex comprising a compound of Formula (I), or a salt thereof, to form an oxidized chelate complex; contacting the oxidized chelate complex with an biological sample; and detecting the analyte in the biological sample. In certain embodiments, the method further comprises covalent binding of the oxidized chelate complex with the analyte.
- In another aspect, provided are kits comprising a compound of Formula (I), or a salt thereof, or a chelate complex comprising a compound of Formula (I). In certain embodiments, the kit further comprises instructions for use.
- The details of certain embodiments of the invention are set forth in the Detailed Description of Certain Embodiments, as described below. Other features, objects, and advantages of the invention will be apparent from the Definitions, Examples, and Claims.
-
FIG. 1 is a series of micrographs showing results of CARD assays employing exemplary compounds of the disclosure. The expression of the intermediate filament protein nestin was detected in normal human kidney podocytes using a goat anti-nestin polyclonal antibody with a rabbit anti-goat secondary horseradish peroxidase/3,3′-diaminobenzidine (DAB) chromogenic assay and standard light microscopy (FIG. 1A ). The chromogenic signal for nestin expression was not seen with negative control conditions including without anti-nestin primary antibody (FIG. 1C ) or without secondary antibody (FIG. 1B ). When DAB was replaced withexemplary compounds FIG. 1E ,FIG. 1I ,FIG. 1M ) or Y3+ (FIG. 1F ,FIG. 1J ,FIG. 1N ), the complex was oxidized by peroxidase and deposited at the site of the anti-nestin antibody. This specific deposition of complex was detected with an anti-DOTA chelate antibody (clone 2D12.5) chromogenic assay using DAB (FIG. 1E ,FIG. 1I ,FIG. 1M ,FIG. 1F ,FIG. 1J ,FIG. 1N ). Empty DOTA was not recognized by the anti-DOTA chelate antibody (clone 2D12.5), therefore chromogenic signal was not seen in these assay conditions (FIG. 1G ,FIG. 1K ,FIG. 1O ). Nestin-specific signal was not seen without anti-DOTA chelate antibody (FIG. 1H ,FIG. 1L ,FIG. 1P ) or without the DOTA chelate complex in the anti-DOTA antibody assay (FIG. 1D ). -
FIG. 2 is a series of images showing detection ofcompounds compound FIG. 2A ,FIG. 2B ) or Y3+ (FIG. 2C ,FIG. 2D ), the complex was oxidized by peroxidase and deposited at the site of the anti-CK7 primary antibody. The deposited complexes were detected. Secondary ion mass spectrometry imaging peaks of Pr3+ (molecular weight=141 g/mol) and Y3+ (molecular weight 88.9=g/mol) containing compounds are shown with adjacent final images from the device (FIGS. 2A-D showing signal in white) comparable to the specific staining of the placental syncytiotrophoblast cells shown with standard DAB staining (FIG. 2H ) and highlighted on a hematoxylin and eosin stained section (FIG. 2I ). The arrow inFIG. 2I refers to the syncytiotrophoblast layer of placenta. As a control, compounds 1 and 3 not chelated to a metal were not recognized by the mass spectrometry imaging device and therefore specific CK7 signal was not seen using these control assay conditions (FIG. 2E ,FIG. 2F ). The dilution of the compound is shown parenthetically. - Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Organic Chemnistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987.
- Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and/or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, E. L., Stereochemistry of Carbon Conpounds (McGraw-Hill, N Y, 1962); and Wilen, S. H., Tables of Resolving Agents and Optical Resolutions, p. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind. 1972). The invention additionally encompasses compounds as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.
-
- Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, replacement of 19F with 18F, or the replacement of 12C with 13C or 14C are within the scope of the disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays.
- When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example “C1-6 alkyl” is intended to encompass, C1, C2, C3, C4, C5, C6, C1-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6 alkyl.
- The term “aliphatic” refers to alkyl, alkenyl, alkynyl, and carbocyclic groups. Likewise, the term “heteroaliphatic” refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.
- The term “alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 10 carbon atoms (“C1-10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1-9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C1-3 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C1-7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1-6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1-5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C1-4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1-3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C1 alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2-6 alkyl”). Examples of C1-6 alkyl groups include methyl (C1), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert-butyl, sec-butyl, iso-butyl), pentyl (C5) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tertiary amyl), and hexyl (C6) (e.g., n-hexyl). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents (e.g., halogen, such as F). In certain embodiments, the alkyl group is an unsubstituted C1-10 alkyl (such as unsubstituted C1-6 alkyl, e.g., —CH3 (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)), unsubstituted butyl (Bu, e.g., unsubstituted n-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec-Bu), unsubstituted isobutyl (i-Bu)). In certain embodiments, the alkyl group is a substituted C1-10 alkyl (such as substituted C1-6 alkyl, e.g., —CF3, Bn).
- The term “haloalkyl” is a substituted alkyl group, wherein one or more of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo. In some embodiments, the haloalkyl moiety has 1 to 8 carbon atoms (“C1-8 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 6 carbon atoms (“C1-6 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 4 carbon atoms (“C1-4 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 3 carbon atoms (“C1-3 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 2 carbon atoms (“C1-2 haloalkyl”). Examples of haloalkyl groups include —CHF2, —CH2F, —CF3, —CH2CF3, —CF2CF3, —CF2CF2CF3, —CCl3, —CFCl2, —CF2Cl, and the like.
- The term “heteroalkyl” refers to an alkyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 20 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-20 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 18 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-18 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 16 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-16 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 14 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-14 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 12 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-12 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 10 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-10 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-8 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-6 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC1-4 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain (“heteroC1-3 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain (“heteroC1-2 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroC1 alkyl”). In some embodiments, the heteroalkyl group defined herein is a partially unsaturated group having 1 or more heteroatoms within the parent chain and at least one unsaturated carbon, such as a carbonyl group. For example, a heteroalkyl group may comprise an amide or ester functionality in its parent chain such that one or more carbon atoms are unsaturated carbonyl groups. Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an “unsubstituted heteroalkyl”) or substituted (a “substituted heteroalkyl”) with one or more substituents. In certain embodiments, the heteroalkyl group is an unsubstituted heteroC1-20 alkyl. In certain embodiments, the heteroalkyl group is an unsubstituted heteroC1-10 alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroC1-20 alkyl. In certain embodiments, the heteroalkyl group is an unsubstituted heteroC1-10 alkyl.
- The term “alkenyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds). In some embodiments, an alkenyl group has 2 to 9 carbon atoms (“C2-9 alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2-8 alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C2-7 alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2-6 alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C2-5 alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C2-4 alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2-3 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C2 alkenyl”). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of C2-4 alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents. In certain embodiments, the alkenyl group is an unsubstituted C2-10 alkenyl. In certain embodiments, the alkenyl group is a substituted C2-10 alkenyl. In an alkenyl group, a C═C double bond for which the stereochemistry is not specified (e.g., —CH═CHCH3 or
- may be an (E)- or (Z)-double bond.
- The term “heteroalkenyl” refers to an alkenyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 10 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-10 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-9 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-8 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-7 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-6 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-5 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-4 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“heteroC2-3 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-6 alkenyl”). Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an “unsubstituted heteroalkenyl”) or substituted (a “substituted heteroalkenyl”) with one or more substituents. In certain embodiments, the heteroalkenyl group is an unsubstituted heteroC2-10 alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroC2-10 alkenyl.
- The term “alkynyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) (“C2-10 alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms (“C2-9alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C2-8 alkynyl”). In some embodiments, an alkynyl group has 2 to 7 carbon atoms (“C2-7 alkynyl”). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C2-6 alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C2-5 alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C2-4 alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C2-3 alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C2 alkynyl”). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of C2-4 alkynyl groups include, without limitation, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkynyl groups as well as pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents. In certain embodiments, the alkynyl group is an unsubstituted C2-10 alkynyl. In certain embodiments, the alkynyl group is a substituted C2-10 alkynyl.
- The term “heteroalkynyl” refers to an alkynyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkynyl group refers to a group having from 2 to 10 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2-10 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2-9 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2-8 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2-7 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2-6 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-5 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-4 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“heteroC2-3 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-6 alkynyl”). Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an “unsubstituted heteroalkynyl”) or substituted (a “substituted heteroalkynyl”) with one or more substituents. In certain embodiments, the heteroalkynyl group is an unsubstituted heteroC2-10 alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroC2-10 alkynyl.
- The term “carbocyclyl” or “carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms (“C3-14 carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms (“C3-10 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C3-8 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C3-7 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms (“C4-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C5-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5-10 carbocyclyl”). Exemplary C3-6 carbocyclyl groups include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C3-8 carbocyclyl groups include, without limitation, the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C3-10 carbocyclyl groups include, without limitation, the aforementioned C3-8 carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and can be saturated or can contain one or more carbon-carbon double or triple bonds. “Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents. In certain embodiments, the carbocyclyl group is an unsubstituted C3-14 carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C3-14 carbocyclyl.
- In some embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 14 ring carbon atoms (“C3-14 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms (“C3-10 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C3-8 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms (“C4-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C5-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C5-10 cycloalkyl”). Examples of C5-6 cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3-6 cycloalkyl groups include the aforementioned C5-6 cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-8 cycloalkyl groups include the aforementioned C3-6 cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents. In certain embodiments, the cycloalkyl group is an unsubstituted C3-14 cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C3-14 cycloalkyl.
- The term “heterocyclyl” or “heterocyclic” refers to a radical of a 3- to 14-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3-14 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g., a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”)), and can be saturated or can contain one or more carbon-carbon double or triple bonds. Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents. In certain embodiments, the heterocyclyl group is an unsubstituted 3-14 membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3-14 membered heterocyclyl.
- In some embodiments, a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
- Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azirdinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing 1 heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing 2 heteroatoms include, without limitation, dioxolanyl, oxathiolanyl and dithiolanyl. Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazinyl. Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary bicyclic heterocyclyl groups include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H-benzo[e][1,4]diazepinyl, 1,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, 1,2,3,4-tetrahydro-1,6-naphthyridinyl, and the like.
- The term “aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14π electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6-14 aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“C6 aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms (“C10 aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms (“C14 aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Unless otherwise specified, each instance of an aryl group is independently unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents. In certain embodiments, the aryl group is an unsubstituted C6-14 aryl. In certain embodiments, the aryl group is a substituted C6-14 aryl.
- “Aralkyl” is a subset of “alkyl” and refers to an alkyl group substituted by an aryl group, wherein the point of attachment is on the alkyl moiety.
- The term “heteroaryl” refers to a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-14 membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused polycyclic (aryl/heteroaryl) ring system. Polycyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).
- In some embodiments, a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents. In certain embodiments, the heteroaryl group is an unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl.
- Exemplary 5-membered heteroaryl groups containing 1 heteroatom include, without limitation, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing 2 heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing 3 heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing 4 heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl groups containing 1 heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing 2 heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing 3 or 4 heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing 1 heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include, without limitation, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl.
- “Heteroaralkyl” is a subset of “alkyl” and refers to an alkyl group substituted by a heteroaryl group, wherein the point of attachment is on the alkyl moiety.
- The term “unsaturated bond” refers to a double or triple bond.
- The term “unsaturated” or “partially unsaturated” refers to a moiety that includes at least one double or triple bond.
- The term “saturated” refers to a moiety that does not contain a double or triple bond, i.e., the moiety only contains single bonds.
- Affixing the suffix “-ene” to a group indicates the group is a divalent moiety, e.g., alkylene is the divalent moiety of alkyl, alkenylene is the divalent moiety of alkenyl, alkynylene is the divalent moiety of alkynyl, heteroalkylene is the divalent moiety of heteroalkyl, heteroalkenylene is the divalent moiety of heteroalkenyl, heteroalkynylene is the divalent moiety of heteroalkynyl, carbocyclylene is the divalent moiety of carbocyclyl, heterocyclylene is the divalent moiety of heterocyclyl, arylene is the divalent moiety of aryl, and heteroarylene is the divalent moiety of heteroaryl.
- A group is optionally substituted unless expressly provided otherwise. The term “optionally substituted” refers to being substituted or unsubstituted. In certain embodiments, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted. “Optionally substituted” refers to a group which may be substituted or unsubstituted (e.g., “substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted” alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or “unsubstituted” heteroalkyl, “substituted” or “unsubstituted” heteroalkenyl, “substituted” or “unsubstituted” heteroalkynyl, “substituted” or “unsubstituted” carbocyclyl, “substituted” or “unsubstituted” heterocyclyl, “substituted” or “unsubstituted” aryl or “substituted” or “unsubstituted” heteroaryl group). In general, the term “substituted” means that at least one hydrogen present on a group is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position. The term “substituted” is contemplated to include substitution with all permissible substituents of organic compounds, and includes any of the substituents described herein that results in the formation of a stable compound. The present invention contemplates any and all such combinations in order to arrive at a stable compound. For purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety. The invention is not intended to be limited in any manner by the exemplary substituents described herein.
- Exemplary carbon atom substituents include, but are not limited to, halogen, —CN, —NO2, —N3, —SO2H, —SO3H, —OH, —ORaa, —ON(Rbb)2, —N(Rbb)2, N(Rbb)3X−, —N(ORcc)Rbb, —SH, —SRaa, —SSRcc, —C(═O)Raa, —CO2H, —CHO, —C(ORcc)3, —CO2Raa, —OC(═O)Raa, —OCO2Raa, —C(═O)N(Rbb)2, —OC(═O)N(Rbb)2, —NRbbC(═O)Raa, —NRbbCO2Raa, —NRbbC(═O)N(Rbb)2, —C(═NRbb)Raa, —C(═NRbb)ORaa, —OC(═NRbb)Raa, —OC(═NRbb)ORaa, —C(═NRbb)N(Rbb)2, —OC(═NRbb)N(Rbb)2, —NRbbC(═NRbb)N(Rbb)2, —C(═O)NRbbSO2Raa, —NRbbSO2R, —SO2N(Rbb)2, —SO2Raa, —SO2ORaa, —OSO2Raa—S(═O)Raa, —OS(═O)Raa, —Si(Raa)3, —OSi(Raa)3—C(═S)N(Rbb)2, —C(═O)SRaa, —C(═S)SRaa, —SC(═S)SRaa, —SC(═O)SRaa, —OC(═O)SRaa, —SC(═O)ORaa, —SC(═O)Raa, —P(═O)(Raa)2, —P(═O)(ORaa)2, —OP(═O)(Raa)2, —OP(═O)(ORcc)2, —P(═O)(N(Rbb)2)2, —OP(═O)(N(Rbb)2)2, —NRbbP(═O)(Raa)2, —NRbbP(═O)(ORcc)2, —NRbbP(═O)(N(Rbb)2)2, —P(Rcc)2, —P(ORcc)2, —P(Rcc)3 +X−, —P(ORcc)+X−, —P(Rcc)4, —P(ORcc)4, —OP(Rcc)2, —OP(Rcc)3 +X−, —OP(ORcc)2, —OP(ORcc)3 +X−, —OP(Rcc)4, —OP(ORcc)4, —B(Raa)2, —B(ORcc)2, —BRaa(ORcc), C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, heteroC1-10 alkyl, heteroC2-10 alkenyl, heteroC2-10 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups; wherein X− is a counterion;
- or two geminal hydrogens on a carbon atom are replaced with the group ═O, ═S, ═NN(Rbb)2, ═NNRbbC(═O)Raa, ═NNRbbC(═O)ORaa, ═NNRbbS(═O)2Raa, ═NRbb, or ═NORcc;
- each instance of Raa is, independently, selected from C1-10 alkyl, C1-10 perhaloalkyl C2-10 alkenyl, C2-10 alkynyl, heteroC1-10 alkyl, heteroC2-10 alkenyl, heteroC2-10 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl C6-14 aryl, and 5-14 membered heteroaryl or two Raa groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups;
- each instance of Rbb is, independently, selected from hydrogen, —OH, —ORaa, —N(Rcc)2, —CN, —C(═O)Raa, —C(═O)N(Rcc)2, —CO2Raa, —SO2Raa, —C(═NRcc)ORaa, —C(═NRcc)N(Rcc)2, —SO2N(Rcc)2, —SO2Rcc, —SO2ORcc, —SORaa, —C(═S)N(Rcc)2, —C(═O)SRcc, —C(═S)SRcc, —P(═O)(Raa)2, —P(═O)(ORcc)2, —P(═O)(N(Rcc)2)2, C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, heteroC1-10 alkyl, heteroC2-10 alkenyl, heteroC2-10 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two Rbb groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups; wherein X is a counterion;
- each instance of Rcc is, independently, selected from hydrogen, C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl C2-10 alkynyl, heteroC1-10 alkyl, heteroC2-10 alkenyl, heteroC2-10 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl C6-14 aryl, and 5-14 membered heteroaryl, or two Rcc groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups;
- each instance of Rdd is, independently, selected from halogen, —CN, —NO2, —N3, —SO2H, —SO3H, —OH, —ORee, —ON(Rff)2, —N(Rff)2, —N(Rff)3 +X−, —N(ORee)Rff, —SH, —SRee, —SSRee, —C(═O)Ree, —CO2H, —CO2Ree, —OC(═O)Ree, —OCO2Ree, —C(═O)N(Rff)2, —OC(═O)N(Rff)2, —NRffC(═O)Ree, —NRffCO2Ree, —NRffC(═O)N(Rff)2, —C(═NRff)ORee, —OC(═NRff)Ree, —OC(═NRff)ORee, —C(═NRff)N(Rff)2, —OC(═NRff)N(Rff)2, —NRffC(═NRff)N(Rff)2, —NRffSO2Ree, —SO2N(Rff)2, —SO2Ree, —SO2ORee, —OSO2Ree, —S(═O)Ree, —Si(Ree)3, —OSi(Rse)3, —C(═S)N(Rff)2, —C(═O)SRee, —C(═S)SRee, —SC(═S)SRee, —P(═O)(ORee)2, —P(═O)(Ree)2, —OP(═O)(Ree)2, —OP(═O)(ORee)2, C1-6 alkyl, C1-6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, heteroC1-6 alkyl, heteroC2-6 alkenyl, heteroC2-6 alkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgg groups, or two geminal Rdd substituents can be joined to form ═O or ═S; wherein X is a counterion;
- each instance of Ree is, independently, selected from C1-6 alkyl, C1-6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, heteroC1-6 alkyl, heteroC2-6 alkenyl, heteroC2-6 alkynyl, C3-10 carbocyclyl, C6-10 aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgg groups;
- each instance of Rff is, independently, selected from hydrogen, C1-6 alkyl, C1-6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, heteroC1-6 alkyl, heteroC2-6 alkenyl, heteroC2-6 alkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, C6-10 aryl and 5-10 membered heteroaryl, or two Rff groups are joined to form a 3-10 membered heterocyclyl or 5-10 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgg groups; and
- each instance of Rgg is, independently, halogen, —CN, —NO2, —N3, —SO2H, —SO3H, —OH, —OC1-6 alkyl, —ON(C1-6 alkyl)2, —N(C1-6 alkyl)2, —N(C1-6 alkyl)3 +X−, —NH(C1-6 alkyl)2 +X−, —NH2(C1-6 alkyl)+X−, —NH3 +X−, —N(OC1-6 alkyl)(C1-6 alkyl), —N(OH)(C1-6 alkyl), —NH(OH), —SH, —SC1-6 alkyl, —SS(C1-6 alkyl), —C(═O)(C1-6 alkyl), —CO2H, —CO2(C1-6 alkyl), —OC(═O)(C1-6 alkyl), —OCO2(C1-6 alkyl), —C(═O)NH2, —C(═O)N(C1-6 alkyl)2, —OC(═O)NH(C1-6 alkyl), —NHC(═O)(C1-6 alkyl), —N(C1-6 alkyl)C(═O)(C1-6 alkyl), —NHCO2(C1-6 alkyl), —NHC(═O)N(C1-6 alkyl)2, —NHC(═O)NH(C1-6 alkyl), —NHC(═O)NH2, —C(═NH)O(C1-6 alkyl), —OC(═NH)(C1-6 alkyl), —OC(═NH)OC1-6 alkyl, —C(═NH)N(C1-6 alkyl)2, —C(═NH)NH(C1-6 alkyl), —C(═NH)NH2, —OC(═NH)N(C1-6 alkyl)2, —OC(═NH)NH(C1-6 alkyl), —OC(═NH)NH2, —NHC(═NH)N(C1-6 alkyl)2, —NHC(═NH)NH2, —NHSO2(C1-6 alkyl), —SO2N(C1-6 alkyl)2, —SO2NH(C1-6 alkyl), —SO2NH2, —SO2(C1-6 alkyl), —SO2O(C1-6 alkyl), —OSO2(C1-6 alkyl), —SO(C1-6 alkyl), —Si(C1-6 alkyl)3, —OSi(C1-6 alkyl)3-C(═S)N(C1-6 alkyl)2, C(═S)NH(C1-6 alkyl), C(═S)NH2, —C(═O)S(C1-6 alkyl), —C(═S)SC1-6 alkyl, —SC(═S)SC1-6 alkyl, —P(═O)(OC1-6 alkyl)2, —P(═O)(C1-6 alkyl)2, —OP(═O)(C1-6 alkyl)2, —OP(═O)(OC1-6 alkyl)2, C1-6 alkyl, C1-6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, heteroC1-6 alkyl, heteroC2-6 alkenyl, heteroC2-6 alkynyl, C3-10 carbocyclyl, C6-10 aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal Rgg substituents can be joined to form ═O or ═S; wherein X− is a counterion.
- The term “halo” or “halogen” refers to fluorine (fluoro, —F), chlorine (chloro, —Cl), bromine (bromo, —Br), or iodine (iodo, —I).
- The term “hydroxyl” or “hydroxy” refers to the group —OH. The term “substituted hydroxyl” or “substituted hydroxyl,” by extension, refers to a hydroxyl group wherein the oxygen atom directly attached to the parent molecule is substituted with a group other than hydrogen, and includes groups selected from —ORaa, —ON(Rbb)2, —OC(═O)SRaa, —OC(═O)Raa, —OCO2Raa, —OC(═O)N(Rbb)2, —OC(═NRbb)Raa, —OC(═NRbb)ORaa, —OC(═NRbb)N(Rbb)2, —OS(═O)Raa, —OSO2Raa, —OSi(Raa)3, —OP(Rcc)2, —OP(Rcc)3 +X−, —OP(ORcc)2, —OP(ORcc)3 +X−, —OP(═O)(Raa)2, —OP(═O)(ORcc)2, and —OP(═O)(N(Rbb)2)2, wherein X−, Raa, Rbb, and Rcc are as defined herein.
- The term “amino” refers to the group —NH2. The term “substituted amino,” by extension, refers to a monosubstituted amino, a disubstituted amino, or a trisubstituted amino. In certain embodiments, the “substituted amino” is a monosubstituted amino or a disubstituted amino group.
- The term “monosubstituted amino” refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with one hydrogen and one group other than hydrogen, and includes groups selected from —NH(Rbb), —NHC(═O)Raa, —NHCO2Raa, —NHC(═O)N(Rbb)2, —NHC(═NRbb)N(Rbb)2, —NHSO2Raa, —NHP(═O)(ORcc)2, and —NHP(═O)(N(Rbb)2)2, wherein Raa, Rbb and Rcc are as defined herein, and wherein Rbb of the group —NH(Rbb) is not hydrogen.
- The term “disubstituted amino” refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with two groups other than hydrogen, and includes groups selected from —N(Rbb)2, —NRbbC(═O)Raa, —NRbbCO2Raa, —NRbbC(═O)N(Rbb)2, —NRbbC(═NRbb)N(Rbb)2, —NRbbSO2Raa, —NRbbP(═O)(ORcc)2, and —NRbbP(═O)(N(Rbb)2)2, wherein Raa, Rbb, and Rcc are as defined herein, with the proviso that the nitrogen atom directly attached to the parent molecule is not substituted with hydrogen.
- The term “trisubstituted amino” refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with three groups, and includes groups selected from —N(Rbb)3 and —N(Rbb)3 +X−, wherein Rbb and X− are as defined herein.
- The term “sulfonyl” refers to a group selected from —SO2N(Rbb)2, —SO2Raa, and —SO2ORaa, wherein Raa and Rbb are as defined herein.
- The term “sulfinyl” refers to the group —S(═O)Raa, wherein Raa is as defined herein.
- The term “acyl” refers to a group having the general formula —C(═O)RX1, —C(═O)ORX1, —C(═O)—O—C(═O)RX1, —C(═O)SRX1, —C(═O)N(RX1)2, —C(═S)RX1, —C(═S)N(RX1)2, —C(═S)O(RX1), —C(═S)S(RX1), —C(═NRX1)RX1, —C(═NRX1)ORX1, —C(═NRX1)SRX1, and —C(═NRX1)N(RX1)2, wherein RX1 is hydrogen; halogen; substituted or unsubstituted hydroxyl; substituted or unsubstituted thiol; substituted or unsubstituted amino; substituted or unsubstituted acyl, cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkyl; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, mono- or di-aliphaticamino, mono- or di-heteroaliphaticamino, mono- or di-alkylamino, mono- or di-heteroalkylamino, mono- or di-arylamino, or mono- or di-heteroarylamino; or two RX1 groups taken together form a 5- to 6-membered heterocyclic ring. Exemplary acyl groups include aldehydes (—CHO), carboxylic acids (—CO2H), ketones, acyl halides, esters, amides, imines, carbonates, carbamates, and ureas. Acyl substituents include, but are not limited to, any of the substituents described herein, that result in the formation of a stable moiety (e.g., aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, oxo, imino, thiooxo, cyano, isocyano, amino, azido, nitro, hydroxyl, thiol, halo, aliphaticamino, heteroaliphaticamino, alkylamino, heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, acyloxy, and the like, each of which may or may not be further substituted).
- The term “carbonyl” refers a group wherein the carbon directly attached to the parent molecule is sp2 hybridized, and is substituted with an oxygen, nitrogen or sulfur atom, e.g., a group selected from ketones (e.g., —C(═O)Raa), carboxylic acids (e.g., —CO2H), aldehydes (—CHO), esters (e.g., —CO2Raa, —C(═O)SRaa, —C(═S)SRaa), amides (e.g., —C(═O)N(Rbb)2, —C(═O)NRbbSO2Raa, —C(═S)N(Rbb)2), and imines (e.g., —C(═NRbb)Raa, —C(═NRbb)ORaa), —C(═NRbb)N(Rbb)2), wherein Raa and Rbb are as defined herein.
- The term “silyl” refers to the group —Si(Raa)3, wherein Raa is as defined herein.
- The term “oxo” refers to the group ═O, and the term “thiooxo” refers to the group ═S.
- Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, —OH, —ORaa, —N(Rcc)2, —CN, —C(═O)Raa, —C(═O)N(Rcc)2, —CO2Raa, —SO2Raa, —C(═NRbb)Raa—C(═NRcc)ORaa, —C(═NRcc)N(Rcc)2, —SO2N(Rcc)2, —SO2Rcc, —SO2ORcc, —SORaa, —C(═S)N(Rcc)2, —C(═O)SRcc, —C(═S)SRcc, —P(═O)(ORcc)2, —P(═O)(Raa)2, —P(═O)(N(Rcc)2)2, C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, heteroC1-10alkyl, heteroC2-10 alkenyl, heteroC2-10alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two Rcc groups attached to an N atom are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups, and wherein Raa, Rbb, Rcc, and Rdd are as defined herein.
- In certain embodiments, the substituent present on the nitrogen atom is an nitrogen protecting group (also referred to herein as an “amino protecting group”). Nitrogen protecting groups include, but are not limited to, —OH, —ORaa, —N(Rcc)2, —C(═O)Raa, —C(═O)N(Rcc)2, —CO2Raa, —SO2Raa, —C(═NRcc)Raa, —C(═NRcc)ORaa, —C(═NRcc)N(Rcc)2, —SO2N(Rcc)2, —SO2Rcc, —SO2ORcc, —SORaa, —C(═S)N(Rcc)2, —C(═O)SRcc, —C(═S)SRcc, C1-10 alkyl (e.g., aralkyl, heteroaralkyl), C2-10 alkenyl, C2-10 alkynyl, heteroC1-10 alkyl, heteroC2-10 alkenyl, heteroC2-10 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl heterocyclyl, aralkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups, and wherein Raa, Rbb, Rcc and Rdd are as defined herein. Nitrogen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
- For example, nitrogen protecting groups such as amide groups (e.g., —C(═O)Raa) include, but are not limited to, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picoiinamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide, p-phenylbenzamide, o-nitophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N′-dithiobenzyloxyacyiamino)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o-mtrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazophenoxylpropanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethionine derivative, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.
- Nitrogen protecting groups such as carbamate groups (e.g., —C(═O)ORaa) include, but are not limited to, methyl carbamate, ethyl carbamate, 9-fluorenyhnethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethyl carbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc), 1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2′- and 4′-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithio carbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p-nitobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc), 1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p-(dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methyl carbamate, t-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate, 2,2-dimethoxyacylvinyl carbamate, o-(N,N-dimethylcarboxamido)benzyl carbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate, 1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborynl carbamate, isobutyl carbamate, isonicotinyl carbamate, p-(p′-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate, 1-methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate, 1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate, 1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethyl carbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzyl carbamate.
- Nitrogen protecting groups such as sulfonamide groups (e.g., —S(═O)2Raa) include, but are not limited to, p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4′,8′-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsuifonamide.
- Other nitrogen protecting groups include, but are not limited to, phenothiazinyl-(10)-acyl derivative, N′-p-toluenesulfonylaminoacyl derivative, N′-phenylaminothioacyl derivative, N-benzoylphenylalanyl derivative, N-acetylmethionine derivative, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted 3,5-dinitro-4-pyridone, N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(l-isopropyl-4-nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylftuorenylamine (PhF), N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm), N-2-picolylamino N′-oxide, N-1,1-dimethylthiomethyleneamine, N-benzylideneamine, N-p-methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, N—(N′,N′-dimethylaminomethylene)amine, N,N′-isopropylidenediamine, N-p-nitrobenzylideneamine, N-salicylideneamine, N-5-chlorosalicylideneamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine, N-borane derivative, N-diphenylborinic acid derivative, N-[phenyl(pentaacylchromium- or tungsten)acyl]amine, N-copper chelate, N-zinc chelate, N-nitroamine, N-nitrosoamine, amine N-oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys). In certain embodiments, a nitrogen protecting group is benzyl (Bn), tert-butyloxycarbonyl (BOC), carbobenzyloxy (Cbz), 9-flurenylmethyloxycarbonyl (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl (Ac), benzoyl (Bz), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), 2,2,2-trichloroethyloxycarbonyl (Troc), triphenylmethyl (Tr), tosyl (Ts), brosyl (Bs), nosyl (Ns), mesyl (Ms), triflyl (Tf), or dansyl (Ds).
- In certain embodiments, the substituent present on an oxygen atom is an oxygen protecting group (also referred to herein as an “hydroxyl protecting group”). Oxygen protecting groups include, but are not limited to, —Raa, —N(Rbb)2, —C(═O)SRaa, —C(═O)Raa, —CO2Raa, —C(═O)N(Rbb)2, —C(═NRbb)Raa, —C(═NRbb)ORaa, —C(═NRbb)N(Rbb)2, —S(═O)Raa, —SO2Raa, —Si(Raa)3, —P(Rcc)2, —P(Rcc)3 +X−, —P(ORcc)2, —P(ORcc)3 +X−, —P(═O)(Raa)2, —P(═O)(ORcc)2, and —P(═O)(N(Rbb)2)2, wherein X−, Raa, Rbb, and Rcc are as defined herein. Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
- Exemplary oxygen protecting groups include, but are not limited to, methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacohnethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethyisilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl (CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxido, diphenylmethyl, p,p′-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4′-bromophenacyloxyphenyl)diphenylmethyl, 4,4′,4″-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4′,4″-tris(levulinoyloxyphenyl)methyl, 4,4,4′,4″-tris(benzoyloxyphenyl)methyl, 3-(imidazol-1-yl)bis(4′,4″-dimethoxyphenyl)methyl, 1,1-bis(4-methoxyphenyl)-1′-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl. 9-(9-phenyl-10-oxo)anthryl, 1,3-benzodithiolan-2-yl, benzisothiazolyl S,S-dioxido, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, 1-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), ethyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl) ethyl carbonate (Psec), 2-(triphenylphosphonio) ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, allyl carbonate, t-butyl carbonate (BOC or Boc), p-nitrophenyl carbonate, benzyl carbonate, p-methoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p-nitrobenzyl carbonate, S-benzyl thiocarbonate, 4-ethoxy-1-napththyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate, o-(methoxyacyl)benzoate, α-naphthoate, nitrate, alkyl N,N,N′,N′-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts). In certain embodiments, an oxygen protecting group is silyl. In certain embodiments, an oxygen protecting group is t-butyldiphenylsilyl (TBDPS), t-butyldimethylsilyl (TBDMS), triisopropylsilyl (TIPS), triphenylsilyl (TPS), triethylsilyl (TES), trimethylsilyl (TMS), triisopropylsiloxymethyl (TOM), acetyl (Ac), benzoyl (Bz), allyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-trimethylsilylethyl carbonate, methoxymethyl (MOM), 1-ethoxyethyl (EE), 2-methyoxy-2-propyl (MOP), 2,2,2-trichloroethoxyethyl, 2-methoxyethoxymethyl (MEM), 2-trimethylsilylethoxymethyl (SEM), methylthiomethyl (MTM), tetrahydropyranyl (THP), tetrahydrofuranyl (THF), p-methoxyphenyl (PMP), triphenylmethyl (Tr), methoxytrityl (MMT), dimethoxytrityl (DMT), allyl, p-methoxybenzyl (PMB), t-butyl, benzyl (Bn), allyl, or pivaloyl (Piv).
- In certain embodiments, the substituent present on a sulfur atom is a sulfur protecting group (also referred to as a “thiol protecting group”). Sulfur protecting groups include, but are not limited to, —Raa, —N(Rbb)2, —C(═O)SRaa, —C(═O)Raa, —CO2Raa, —C(═O)N(Rbb)2, —C(═NRbb)Raa, —C(═NRbb)ORaa, —C(═NRbb)N(Rbb)2, —S(═O)Raa, —SO2Raa, —Si(Raa)3, —P(Rcc)2, —P(Rcc)3 +X−, —P(ORcc)2, —P(ORcc)3 +X−, —P(═O)(Raa)2, —P(═O)(ORcc)2, and —P(═O)(N(Rbb)2)2, wherein Raa, Rbb, and Rcc are as defined herein. Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rd edition, John Wiley & Sons, 1999, incorporated herein by reference. In certain embodiments, a sulfur protecting group is acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl.
- A “counterion” or “anionic counterion” is a negatively charged group associated with a positively charged group in order to maintain electronic neutrality. An anionic counterion may be monovalent (i.e., including one formal negative charge). An anionic counterion may also be multivalent (i.e., including more than one formal negative charge), such as divalent or trivalent. Exemplary counterions include halide ions (e.g., F−, Cl−, Br−, I−), NO3 −, ClO4 −, OH−, H2PO4 −, HCO3 − HSO4 −, sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphor sulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate, ethan-1-sulfonic acid-2-sulfonate, and the like), carboxylate ions (e.g., acetate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate, and the like), BF4 −, PF4 −, PF6 −, AsF6 −, SbF6 −, B[3,5-(CF3)2C6H3]4]−, B(C6F5)4 −, BPh4 −, Al(OC(CF3)3)4 −, and carborane anions (e.g., CB11H12 − or (HCB11Me5Br6)−). Exemplary counterions which may be multivalent include CO3 2−, HPO4 2−, PO4 −, B4O7 2−, SO4 2−, S2O3 2−, carboxylate anions (e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like), and carboranes.
- The term “leaving group” is given its ordinary meaning in the art of synthetic organic chemistry and refers to an atom or a group capable of being displaced by a nucleophile. See, for example, Smith, March's Advanced Organic Chemistry 6th ed. (501-502). Examples of suitable leaving groups include, but are not limited to, halogen (such as F, Cl, Br, or I (iodine)), alkoxycarbonyloxy, aryloxycarbonyloxy, alkanesulfonyloxy, arenesulfonyloxy, alkyl-carbonyloxy (e.g., acetoxy), arylcarbonyloxy, aryloxy, methoxy, N,O-dimethylhydroxylamino, pixyl, and haloformates. In some cases, the leaving group is a sulfonic acid ester, such as toluenesulfonate (tosylate, —OTs), methanesulfonate (mesylate, —OMs), p-bromobenzenesulfonyloxy (brosylate, —OBs), —OS(═O)2(CF2)3CF3 (nonaflate, —ONf), or trifhioromethanesulfonate (triflate, —OTf). In some cases, the leaving group is a brosylate, such as p-bromobenzenesulfonyloxy. In some cases, the leaving group is a nosylate, such as 2-nitrobenzenesulfonyloxy. The leaving group may also be a phosphineoxide (e.g., formed during a Mitsunobu reaction) or an internal leaving group such as an epoxide or cyclic sulfate. Other non-limiting examples of leaving groups are water, ammonia, alcohols, ether moieties, thioether moieties, zinc halides, magnesium moieties, diazonium salts, and copper moieties. Further exemplary leaving groups include, but are not limited to, halo (e.g., chloro, bromo, iodo) and activated substituted hydroxyl groups (e.g., —OC(═O)SRaa, —OC(═O)Raa, —OCO2Raa, —OC(═O)N(Rbb)2, —OC(═NRbb)Raa, —OC(═NRbb)ORaa, —OC(═NRbb)N(Rbb)2, —OS(═O)Raa, —OSO2Raa, —OP(Rcc)2, —OP(Rcc)3, —OP(═O)2Raa, —OP(═O)(Raa)2, —OP(═O)(ORcc)2, —OP(═O)2N(Rbb)2, and —OP(═O)(NRbb)2, wherein Raa, Rbb, and Rcc are as defined herein).
- As used herein, use of the phrase “at least one instance” refers to 1, 2, 3, 4, or more instances, but also encompasses a range, e.g., for example, from 1 to 4, from 1 to 3, from 1 to 2, from 2 to 4, from 2 to 3, or from 3 to 4 instances, inclusive.
- A “non-hydrogen group” refers to any group that is defined for a particular variable that is not hydrogen.
- These and other exemplary substituents are described in more detail in the Detailed Description, Examples, and claims. The invention is not intended to be limited in any manner by the above exemplary listing of substituents.
- The following definitions are more general terms used throughout the present application.
- As used herein, the terms “amplify” and “amplification” as used herein means amplification of reporter signal.
- As used herein, the term “deposition” means directed binding of a reactive intermediate to the receptor which results from the formation of a covalent bond.
- As used herein, the term “reactive intermediate” means the substrate portion of the conjugate has been primed by the enzyme to bind to the receptor. In the compounds of the disclosure, the phenolic moiety is converted to the reactive intermediate, which can bind to the receptor.
- As used herein, the term “salt” refers to any and all salts, and encompasses pharmaceutically acceptable salts.
- The term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate-ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N+(C1-4 alkyl)4 − salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.
- The term “solvate” refers to forms of the compound, or a salt thereof, that are associated with a solvent, usually by a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. The compounds described herein may be prepared, e.g., in crystalline form, and may be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of a crystalline solid. “Solvate” encompasses both solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates, and methanolates.
- The term “hydrate” refers to a compound that is associated with water. Typically, the number of the water molecules contained in a hydrate of a compound is in a definite ratio to the number of the compound molecules in the hydrate. Therefore, a hydrate of a compound may be represented, for example, by the general formula R·x H2O, wherein R is the compound, and x is a number greater than 0. A given compound may form more than one type of hydrate, including, e.g., monohydrates (x is 1), lower hydrates (x is a number greater than 0 and smaller than 1, e.g., hemihydrates (R·0.5 H2O)), and polyhydrates (x is a number greater than 1, e.g., dihydrates (R·2 H2O) and hexahydrates (R·6 H2O)).
- The term “tautomers” or “tautomeric” refers to two or more interconvertible compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valency (e.g., a single bond to a double bond, a triple bond to a single bond, or vice versa). The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Tautomerizations (i.e., the reaction providing a tautomeric pair) may catalyzed by acid or base. Exemplary tautomerizations include keto-to-enol, amide-to-imide, lactam-to-lactim, enamine-to-imine, and enamine-to-(a different enamine) tautomerizations.
- It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”.
- Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (−)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.
- The term “polymorph” refers to a crystalline form of a compound (or a salt, hydrate, or solvate thereof). All polymorphs have the same elemental composition. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form to dominate. Various polymorphs of a compound can be prepared by crystallization under different conditions.
- The term “biological sample” refers to any sample including tissue samples (such as tissue sections and needle biopsies of a tissue); cell samples (e.g., cytological smears (such as Pap or blood smears) or samples of cells obtained by microdissection); samples of whole organisms (such as samples of yeasts or bacteria); or cell fractions, fragments or organelles (such as obtained by lysing cells and separating the components thereof by centrifugation or otherwise). Other examples of biological samples include blood, serum, urine, semen, fecal matter, cerebrospinal fluid, interstitial fluid, mucous, tears, sweat, pus, biopsied tissue (e.g., obtained by a surgical biopsy or needle biopsy), nipple aspirates, milk, vaginal fluid, saliva, swabs (such as buccal swabs), or any material containing biomolecules that is derived from a first biological sample.
- The term “tissue” refers to any biological tissue of a subject (including a group of cells, a body part, or an organ) or a part thereof, including blood and/or lymph vessels, which is the object to which a compound, particle, and/or composition of the invention is delivered. A tissue may be an abnormal or unhealthy tissue, which may need to be treated. A tissue may also be a normal or healthy tissue that is under a higher than normal risk of becoming abnormal or unhealthy, which may need to be prevented. In certain embodiments, the tissue is the central nervous system. In certain embodiments, the tissue is the brain.
- Provided herein are compounds, salts, and chelate complexes that are useful in methods of catalyzed reporter deposition for detection of analytes in biological samples. In one aspect, the disclosure provides compounds of Formula (I), and salts, chelate complexes, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and compositions thereof. In certain embodiments, the disclosure provides chelate complexes comprising the compounds of Formula (I) and a metal cation.
- The compounds described herein possess hydrogen donating moieties that can be oxidized when contacted with an enzyme activation system (e.g., a peroxidase). The oxidized compound is useful in methods of catalyzed reporter deposition for the detection of analytes in biological samples. In particular, the macrocyclic DOTA moiety functions as a reporter group which can be detected by a variety of detection methods (e.g., mass spectrometry based imaging). The compounds are particularly useful in the methods and uses described herein when the DOTA moiety comprises a chelate complex having a metal counterion (e.g., lanthanides, yttrium, praesodynium). The DOTA-containing compounds and complexes are advantageous over existing reporter compounds and complexes because the DOTA moiety allows detection of the reporter moiety by use of mass spectrometry imaging microscopy. A compound may be provided for use in any composition, kit, or method described herein as a salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or chelate complex thereof.
- In one aspect, disclosed is a compound of Formula (I):
- or a salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or chelate complex thereof, wherein:
- G is a chelating moiety;
- R1 is substituted or unsubstituted alkylene, a bond, —O—, —S—, or —NRA—;
- R2 is a bond, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
- X1 is a bond or N;
- X is O or S;
- R5 is hydrogen, substituted or unsubstituted C1-C6 alkyl, or a nitrogen protecting group;
- R4 is substituted or unsubstituted C2-C6 heteroaliphatic, substituted or unsubstituted C2-C6 alkylene, substituted or unsubstituted C2-C6 alkenylene, or substituted or unsubstituted C2-C6 alkynylene;
- R5 is hydrogen, halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —N(RA)2, or —ORA;
- R6 is hydrogen, halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —N(RA)2, or —ORA;
- R7 is hydrogen, halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —N(RA)2, or —ORA;
- R8 is hydrogen, halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —N(RA)2, or —ORA; and
- each occurrence of RA is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, a nitrogen protecting group when attached to a nitrogen atom, or an oxygen protecting group when attached to a nitrogen atom, or two RA groups are joined to form a substituted or unsubstituted heterocyclic ring.
- Chelation is a type of bonding of ions and molecules to metal ions. It involves the formation or presence of coordinate bonds between a ligand and a single central atom. In certain embodiments, the ligand may be polydentate, or multiply bonded. Typically, these ligands are organic compounds, and are called chelants, chelators, chelating agents, or sequestering agents.
- As generally defined herein, G is a chelating moiety. In certain embodiments, G comprises amino acid moieties that act as chelating atoms. In certain embodiments, G is a heterocyclic moiety. In certain embodiments, G is an acyclic moiety. In certain embodiments, G is capable of forming a chelate complex with a metal ion.
- In certain embodiments, G is of the formula
- In certain embodiments, G is of the formula
- As generally defined herein, R1 is substituted or unsubstituted alkylene, a bond, —O—, —S—, or —NRA—. In certain embodiments, R1 is substituted or unsubstituted alkylene. In certain embodiments, R1 is substituted or unsubstituted C1-C6 alkylene. In certain embodiments, R1 is unsubstituted C1-C6 alkylene. In certain embodiments, R1 is unsubstituted C1-C5 alkylene. In certain embodiments, R1 is unsubstituted C1-C4 alkylene. In certain embodiments, R1 is unsubstituted C1-C3 alkylene. In certain embodiments, R1 is unsubstituted C1-C2 alkylene. In certain embodiments, R1 is methylene. In certain embodiments, R1 is ethylene. In certain embodiments, R1 is propylene. In certain embodiments, R1 is butylene. In certain embodiments, R1 is pentylene. In certain embodiments, R1 is hexylene.
- As generally defined herein, R2 is a bond, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene. In certain embodiments, R2 is substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene. In certain embodiments, R2 is substituted or unsubstituted carbocyclylene. In certain embodiments, R2 is substituted or unsubstituted heterocyclylene. In certain embodiments, R2 is substituted or unsubstituted arylene or substituted or unsubstituted heteroarylene. In certain embodiments, R2 is substituted or unsubstituted arylene. In certain embodiments, R2 is unsubstituted arylene. In certain embodiments, R2 is substituted or unsubstituted phenylene. In certain embodiments, R2 is unsubstituted phenylene.
- In certain embodiments, R1 is substituted or unsubstituted C1-C6 alkylene and R2 is substituted or unsubstituted phenylene. In certain embodiments, R1 is unsubstituted C1-C6 alkylene and R2 is unsubstituted phenylene.
- As generally defined herein, X is O or S. In certain embodiments, X is O. In certain embodiments, X is S.
- In certain embodiments, R1 is substituted or unsubstituted G-G alkylene; R2 is substituted or unsubstituted phenylene; and X is O. In certain embodiments, R1 is unsubstituted C1-C6 alkylene; R2 is unsubstituted phenylene; and X is O.
- In certain embodiments, R1 is substituted or unsubstituted C1-C6 alkylene; R2 is substituted or unsubstituted phenylene; and X is S. In certain embodiments, R1 is unsubstituted C1-C6 alkylene; R2 is unsubstituted phenylene; and X is S.
- As generally defined herein, X1 is a bond or N. In certain embodiments, X1 is A bond. In certain embodiments, X1 is N.
- As generally defined herein, R3 is hydrogen, substituted or unsubstituted C1-C6 alkyl, or a nitrogen protecting group. In certain embodiments, R3 is substituted or unsubstituted C1-C6 alkyl. In certain embodiments, R3 is unsubstituted C1-C6 alkyl. In certain embodiments, R3 is unsubstituted C1-C2 alkyl. In certain embodiments, R3 is unsubstituted C1-C4 alkyl. In certain embodiments, R2 is unsubstituted C1-C3 alkyl. In certain embodiments, R3 is unsubstituted C1-C2 alkyl. In certain embodiments, R3 is methyl. In certain embodiments, R3 is ethyl. In certain embodiments, R3 is propyl. In certain embodiments, R3 is butyl. In certain embodiments, R3 is pentyl. In certain embodiments, R3 is hexyl. In certain embodiments, R3 is a nitrogen protecting group. In certain embodiments, R3 is hydrogen.
- In certain embodiments, R1 is substituted or unsubstituted C1-C6 alkylene; R2 is substituted or unsubstituted phenylene; and X is O. In certain embodiments, R1 is unsubstituted C1-C6, alkylene; R2 is unsubstituted phenylene; X is O; and R2 is hydrogen.
- In certain embodiments, R1 is substituted or unsubstituted C1-C6 alkylene; R2 is substituted or unsubstituted phenylene; and X is S. In certain embodiments, R1 is unsubstituted C1-C6 alkylene; R2 is unsubstituted phenylene; X is S; and R3 is hydrogen.
- As generally defined herein, R4 is substituted or unsubstituted C2-C6 heteroaliphatic, substituted or unsubstituted C2-C6 alkylene, substituted or unsubstituted C1-C6 alkenylene, or substituted or unsubstituted C2-C6 alkynylene. In certain embodiments, R4 is substituted or unsubstituted C2-C6 heteroaliphatic, substituted or unsubstituted C1-C6 alkylene, or substituted or unsubstituted C2-C6 alkenylene. In certain embodiments, R4 is unsubstituted C2-C6 heteroaliphatic, unsubstituted C2-C6 alkylene, or unsubstituted C2-C6 alkenylene. In certain embodiments, R4 is unsubstituted C2-C6 heteroalkylene, unsubstituted C2-C0 alkylene, or unsubstituted C2-C6 alkenylene.
- In certain embodiments, R4 is unsubstituted C2-C6 alkylene. In certain embodiments, R4 is unsubstituted C2-C5 alkylene. In certain embodiments, R4 is unsubstituted C2-C4 alkylene. In certain embodiments, R4 is unsubstituted C2-C3 alkylene. In certain embodiments, R4 is unsubstituted ethylene.
- In certain embodiments, R4 is unsubstituted C2-G, alkenylene. In certain embodiments, R4 is unsubstituted C2-C5 alkenylene. In certain embodiments, R4 is unsubstituted C2-C4 alkenylene. In certain embodiments, R4 is unsubstituted C2-C3 alkenylene. In certain embodiments, R4 is unsubstituted ethenylene.
- In certain embodiments, R4 is substituted or unsubstituted C2-C6 heteroalkylene. In certain embodiments, R4 is unsubstituted C2-C6 heteroalkylene. In certain embodiments, R4 is unsubstituted C2-C5 heteroalkylene. In certain embodiments, R4 is unsubstituted C2-C4 heteroalkylene. In certain embodiments, R4 is unsubstituted C2-C3 heteroalkylene. In certain embodiments, R4 is unsubstituted C2 heteroalkylene. In certain embodiments, R4 is of the formula
- wherein Q is O, NR20, S, S(O), or S(O)2, and R20 is hydrogen or C6-C6 alkyl. In certain embodiments, R4 is
- In certain embodiments, R4 is
- Groups R5-R8
- As generally defined herein, R5, R6, R7, and R8 are each independently hydrogen, halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —N(RA)2, or —ORA.
- In certain embodiments, R5, R6, R7, and R8 are independently hydrogen, halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyl, —N(RA)2, or —ORA. In certain embodiments, R5, R6, R7, and R8 are independently hydrogen, halogen, nitro, cyano, unsubstituted alkyl, unsubstituted alkenyl, —N(RA)2, or —ORA. In certain embodiments, R5, R6, R7, and R8 are independently hydrogen, halogen, nitro, cyano, unsubstituted C1-C6 alkyl, unsubstituted C2-C4 alkenyl, —N(RA)2, or —ORA.
- In certain embodiments, R5, R6, R7, and R8 are independently hydrogen, —N(RA)2, or —ORA In certain embodiments, R5, R6, R7, and R8 are independently hydrogen, —N(RA)2, or —ORA; and each RA is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, a nitrogen protecting group, or an oxygen protecting group. In certain embodiments, R5, R6, R7, and R8 are independently hydrogen, —N(RA)2, or —ORA; and each RA is independently hydrogen, substituted or unsubstituted acyl, a nitrogen protecting group, or an oxygen protecting group. In certain embodiments, R5, R6, R7, and R8 are independently hydrogen, —N(RA)2, or —ORA; and each RA is independently hydrogen, a nitrogen protecting group, or an oxygen protecting group. In certain embodiments, R5, R6, R7, and R8 are independently hydrogen, —N(RA)2, or —ORA; and each RA is hydrogen. In certain embodiments, R5, R6, R7, and R8 are independently hydrogen or —ORA; and RA is hydrogen.
- In certain embodiments, at least one of R5, R6, R7, and R8 is —ORA. In certain embodiments, at least one of R5, R6, R7, and R8 is —OH. In certain embodiments, two of R5, R6, R7, and R8 are —ORA. In certain embodiments, two of R5, R6, R7, and R8 are —OH. In certain embodiments, R5 and R8 are hydrogen; and R6 and R7 are independently hydrogen or —ORA. In certain embodiments, R5, R7, and R8 are each hydrogen. In certain embodiments, R5, R7, and R8 are each hydrogen; and R6 is hydrogen or —ORA. In certain embodiments, R5, R7, and R8 are each hydrogen; and R6 is hydrogen or —OH. In certain embodiments, R5, R6, R7, and R8 are each hydrogen.
- In certain embodiments, the compound of Formula (I) is a compound of Formula (I-a):
- or a salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or chelate complex thereof, wherein R1, R2, R3, X, R4, R5, R6, R7, R8, and RA are as defined herein.
- In certain embodiments, the compound of Formula (I) is a compound of Formula (I-b):
- or a salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or chelate complex thereof, wherein R1, R2, R3, X, R4, R5, R6, R7, R8, and RA are as defined herein.
- In certain embodiments, the compound of Formula (I) is a compound of Formula (I-c):
- or a salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or chelate complex thereof, wherein R3, X, R4, R5, R6, R7, R8, and RA are as defined herein.
- In certain embodiments, the compound of Formula (I) is a compound of Formula (I-d):
- or a salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or chelate complex thereof, wherein R4, R5, R6, R7, R8, and RA are as defined herein.
- In certain embodiments, the compound of Formula (I) is a compound of Formula (I-e):
- or a salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or chelate complex thereof, wherein R5, R6, R7, R8, and RA are as defined herein.
- In certain embodiments, the compound of Formula (I) is a compound of Formula (I-f):
- or a salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or chelate complex thereof, wherein R6 and RA are as defined herein.
- In certain embodiments, the compound of Formula (I) is a compound of Formula (I-g):
- or a salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or chelate complex thereof, wherein R1, R2, and R3 are as defined herein.
- In certain embodiments, the compound of Formula (I) is a compound of Formula (I-h):
- or a salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or chelate complex thereof, wherein R5, R6, R7, R8, and RA are as defined herein.
- In certain embodiments, the compound of Formula (I) is a compound of Formula (I-i):
- or a salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or chelate complex thereof, wherein R6 and RA are as defined herein.
- In certain embodiments, the compound of Formula (I) is a compound of Formula
- or a salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or chelate complex thereof, wherein R1, R2, and R3 are as defined herein.
- In certain embodiments, the compound of Formula (I) is a compound of Formula (I-k):
- or a salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or chelate complex thereof, wherein R4, R5, R6, R7, R8, and RA are as defined herein.
- In certain embodiments, the compound of Formula (I) is a compound of Formula (I-l):
- or a salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or chelate complex thereof, wherein R5, R6, R7, R8, and RA are as defined herein.
- In certain embodiments, the compound of Formula (I) is a compound of Formula (I-m):
- or a salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or chelate complex thereof, wherein R6 and RA are as defined herein.
- In certain embodiments, the compound of Formula (I) is a compound of Formula (I-n):
- or a salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or chelate complex thereof, wherein R1, R2, and R3 are as defined herein.
- In certain embodiments, the compound of Formula I is a compound of Table 1, or a salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or chelate complex thereof.
- In another aspect, disclosed are salts of the compound of Formula (I). In certain embodiments, the salt comprises a metal counterion, hi certain embodiments, the metal counterion is bismuth, lead, yttrium, cadmium, mercury, actinium, thorium, strontium, or a lanthanide. In certain embodiments, the metal counterion has an oxidation state of +3. In certain embodiments, the metal counterion is yttrium, praseodymium, or lutetium. In certain embodiments, the metal counterion is yttrium. In certain embodiments, the metal counterion is Y3+. In certain embodiments, the metal counterion is praseodymium. In certain embodiments, the metal counterion is P3+.
- In another aspect, disclosed are chelate complexes comprising the compound of Formula (I) or a salt thereof. A chelate complex is a chemical compound composed of a metal ion and a chelating agent. A chelating agent forms one or more bonds to a single metal ion. In the present disclosure, the compound of Formula (I) may be a chelating agent. In certain embodiments, the chelate complex comprising a compound of Formula (I), or a salt thereof, is a monovalent chelate complex. In certain embodiments, the chelate complex comprising a compound of Formula (I), or a salt thereof, is a divalent chelate complex. In certain embodiments, the chelate complex comprising a compound of Formula (I), or a salt thereof, is a trivalent chelate complex.
- In certain embodiments, the metal ion is bismuth, lead, yttrium, cadmium, mercury, actinium, thorium, strontium, or a lanthanide, hi certain embodiments, the metal ion is yttrium, praseodymium, or lutetium. In certain embodiments, the metal ion has an oxidation state of +3. In certain embodiments, the metal ion is yttrium. In certain embodiments, the metal ion is Y3+. In certain embodiments, the metal ion is praseodymium. In certain embodiments, the metal ion is P3+.
- In certain embodiments, the chelate complex comprising the compound of Formula (I), or a salt thereof, is any of the formula of Table 2.
- Also encompassed by the disclosure are kits. The kits provided may comprise a compound, salt, or chelate complex described herein and a container (e.g., a vial, ampule, bottle, syringe, and/or dispenser package, or other suitable container). In certain embodiments, the kit further comprises an activating enzyme. In certain embodiments, the enzyme is a peroxidase. In certain embodiments, the enzyme is horseradish peroxidase.
- Thus, in one aspect, provided are kits including a container comprising a compound, salt, or chelate complex described herein. In certain embodiments, the kits are useful for assaying methods to detect an analyte (e.g., a protein from human tissue, nucleic acids). In certain embodiments, a kit described herein further includes instructions for using the kit.
- Provided herein are DOTA-containing compounds (e.g., compounds of Formula (I)) and complexes that are reactive with an enzyme activator (e.g., a peroxidase) and covalently bind a target analyte (e.g., a protein, nucleic acids) in a catalyzed reporter deposition assaying method. The macrocyclic DOTA portion of the molecule may then act as a reporter group which can be detected directly (e.g., mass spectrometry based imaging) or indirectly (e.g., DOTA antibody coupled to chromogenic deposition of a light-emitting compound and visualization with light or fluorescence microscopy). The compounds are most useful in the methods and uses described herein when they comprise a chelate complex having a metal counterion (e.g., lanthanides, yttrium, praesodynium). The DOTA-containing compounds and complexes are advantageous over existing reporter compounds and complexes because the DOTA moiety allows detection of the reporter moiety by use of mass spectrometry imaging microscopy.
- In one aspect, disclosed is a method of detecting an analyte, the method comprising: reacting an enzyme with a chelate complex (e.g., comprising a compound of Formula (I)) described herein to form an oxidized chelate complex; contacting the oxidized chelate complex with a biological sample; and detecting the analyte in the biological sample.
- In certain embodiments, the method further comprises covalent binding of the oxidized chelate complex with the analyte.
- In certain embodiments, the biological sample is immobilized.
- In certain embodiments, the analyte comprises a protein derived from human tissue.
- In certain embodiments, the enzyme is a peroxidase. In certain embodiments, the enzyme is horseradish peroxidase. In certain embodiments, the analyte does not react with the enzyme.
- In certain embodiments, the detecting of the analyte is direct or indirect. In certain embodiments, the detecting of the analyte is indirect. In certain embodiments, the detecting of the analyte comprises adding a DOTA chelate-specific antibody coupled to chromogenic deposition of a light-emitting compound (e.g., 3,3′-diaminobenzidine tetrahydrochloride) and visualization with light or fluorescence microscopy.
- In certain embodiments, the detecting of the analyte is direct. In certain embodiments, the detecting of the analyte comprises mass spectrometry imaging based microscopy. In certain embodiments, the detecting is achieved by employing mass spectrometry imaging based microscopy. In certain embodiments, the detecting is achieved by employing multiplexed ion beam imaging (MIBI). In certain embodiments, the detecting is achieved by employing Imaging Mass Cytometry™ (IMC™).
- In order that the invention described herein may be more fully understood, the following examples are set forth. The examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting their scope.
- Compounds of Formula I may be prepared using the synthetic schemes described below.
-
Compound 1 was prepared by the following synthetic scheme. -
Compound 2 was prepared by the following synthetic scheme. -
Compound 3 was prepared by the following synthetic scheme. - Metal loading of the exemplary compounds was accomplished by the following scheme.
- Assays were performed to demonstrate the ability of chelate complexes of the exemplary compounds to function in a catalyzed reporter deposition assaying method.
- Tables A-F below describe the stepwise procedure of the assays.
- Table A (anti-nestin positive control) provides the assay procedure for demonstrating the expression of the intermediate filament protein nestin detected in normal human kidney podocytes using a goat anti-nestin polyclonal antibody with a rabbit anti-goat secondary horseradish peroxidase/3,3′-diaminobenzidine (DAB) chromogenic assay and standard light microscopy (
FIG. 1A ). - Tables B and C provide the assay procedures for demonstrating that the chromogenic signal for nestin expression is not seen with negative control conditions including without anti-nestin primary antibody (Table C;
FIG. 1C ) or without secondary antibody (Table B;FIG. 1B ). - Table D provides the assay procedure for demonstrating that the nestin-specific signal is not seen without the DOTA chelate complex in the anti-DOTA antibody assay (
FIG. 1D ). - Table E provides the assay procedure for evaluating
exemplary compounds FIG. 1E ,FIG. 1I ,FIG. 1M ) or Y3+ (FIG. 1F ,FIG. 1J ,FIG. 1N ) or not complexed (FIG. 1G ,FIG. 1K ,FIG. 1O ). In each assay the complex was oxidized by peroxidase and deposited at the site of the anti-nestin antibody. This specific deposition of complex was detected with an anti-DOTA chelate antibody (clone 2D12.5) chromogenic assay using DAB. Empty DOTA is not recognized by the anti-DOTA chelate antibody (clone 2D12.5), therefore chromogenic signal was not seen in these assay conditions (FIG. 1G ,FIG. 1K ,FIG. 1O ). - Table F provides the assay procedure for evaluating
exemplary compounds FIG. 1H ,FIG. 1L ,FIG. 1P ) but without addition of the anti-DOTA antibody to the assay. Nestin-specific signal was not seen without anti-DOTA chelate antibody (FIG. 1H ,FIG. 1L ,FIG. 1P ). -
FIG. 2 confirms that the disclosed compounds can be detected by a mass spectrometry imaging device in an assay. Images were generated using a MIBIscope I multiplexed ion beam imaging device from IONpath (Menlo Park, Calif.). The parenthetical terms 1:4K, 1:2K, and 1:1K refer to the dilution of the compound used in the assay. In particular, compounds 1 and 3 complexed to Pr3+ (FIGS. 2A, 2C ) or Y3+ (FIGS. 2B, 2D ) were detected directly in human placenta samples using the mass spectrometry imaging device. -
TABLE A Step Reagent Inc. (min): Temperature: Supplier Santo Cruze 1 Goat anti- 30:00 Ambient Cat# SC-21248; human Lot# A2313 NESTIN Dispense type: 150 μL Step type: Reagent Step Reagent Inc. (min): Temperature: Supplier: Leica 2 *BondWashSolution 0:00 Ambient Microsystems Step type: Wash Dispense type. 150 μL Step Reagent Inc. (min): Temperature: Supplier: Leica 3 *BondWashSolution 0:00 Ambient Microsystems Step type: Wash Dispense type. 150 μL Step Reagent Inc. (min): Temperature: Supplier: Leica 4 *BondWashSolution 0:00 Ambient Microsystems Step type: Wash Dispense type. 150 μL Step Reagent Inc. (min): Temperature: Supplier: Leica 5 *BondWashSolution 2:00 Ambient Microsystems Step type: Wash Dispense type. 150 μL Step Reagent Inc. (min): Temperature: Supplier: Leica 6 *BondWashSolution 2:00 Ambient Microsystems Step type: Wash Dispense type. 150 μL Step Reagent Inc. (min): Temperature: Supplier: Leica 7 *BondWashSolution 2:00 Ambient Microsystems Step type: Wash Dispense type. 150 μL Step Reagent Inc. (min): Temperature: Supplier: Vector Lab 8 Rabbit anti- 8:00 Ambient Cat# BA-5000 goat IgG Dispense type: 150 μL Step type: Reagent Step Reagent Inc. (min): Temperature: Supplier: Leica 9 *BondWashSolution 2:00 Ambient Microsystems Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): Temperature: Supplier: Leica 10 *BondWashSolution 2:00 Ambient Microsystems Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): Temperature: Supplier: Leica 11 *BondWashSolution 2:00 Ambient Microsystems Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): Temperature: Supplier: Leica 12 *Polymer 8:00 Ambient Microsystems Step type: Reagent Dispense type: 150 μL Step Reagent Inc. (min): Temperature: Supplier: Leica 13 *BondWashSolution 2:00 Ambient Microsystems Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): Temperature: Supplier: Leica 14 *BondWashSolution 2:00 Ambient Microsystems Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): Temperature: Supplier: Leica 15 *BondWashSolution 2:00 Ambient Microsystems Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): Temperature: Supplier: Leica 16 *BondWashSolution 0:00 Ambient Microsystems Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): Temperature: Supplier: Leica 17 *Peroxide Block 5:00 Ambient Microsystems Step type: Reagent Dispense type: 150 μL Step Reagent Inc. (min): Temperature: Supplier: Leica 18 *BondWashSolution 0:00 Ambient Microsystems Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): Temperature: Supplier: Leica 19 *BondWashSolution 0.00 Ambient Microsystems Step type: Wash Dispense type. Open Step Reagent Inc. (min): Temperature: Supplier: Leica 20 *BondWashSolution 0:00 Ambient Microsystems Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): Temperature: Supplier: Not applicable 21 *Deionized Water 0:00 Ambient Dispense type: 150 μL Step type: Reagent Step Reagent Inc. (min): Temperature: Supplier: Not applicable 22 *Delonized Water 0:00 Ambient Dispense type: 150 μL Step type: Wash Step Reagent Inc. (min): Temperature: Supplier: Leica 23 *MixedDABRefine 2:00 Ambient Microsystems Step type: Reagent Dispense type: 150 μL Step Reagent Inc. (min): Temperature: Supplier: Leica 24 *MixedDABRefine 5:00 Ambient Microsystems Step type: Reagent Dispense type: 150 μL Step Reagent Inc. (min): Temperature: Supplier: Not applicable 25 *Deionized Water 0:00 Ambient Dispense type: 150 μL Step type: Wash Step Reagent Inc. (min): Temperature: Supplier: Not applicable 26 *Deionized Water 0:00 Ambient Dispense type: 150 μL Step type: Wash Step Reagent Inc. (min): Temperature: Supplier: Not applicable 27 *Deionized Water 0:00 Ambient Dispense type: 150 μL Step type: Wash Step Reagent Inc. (min): Temperature: Supplier: Leica 28 *Hematoxylin 10:00 Ambient Microsystems Step type: Reagent Dispense type: 150 μL Step Reagent Inc. (min): Temperature: Supplier: Not applicable 29 *Deionized Water 0:00 Ambient Dispense type: 150 μL Step type: Wash Step Reagent Inc. (min): Temperature: Supplier: Leica 30 *BondWashSolution 1:00 Ambient Microsystems Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): Temperature: Supplier: Leica 31 *BontWashSolution 0:00 Ambient Microsystems Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): Temperature: Supplier: Not applicable 32 *Deionized Water 0:00 Ambient Dispense type: 150 μL Step type: Wash -
TABLE B Step Reagent Inc. (min): 30:00 Temperature: Ambient Supplier: Santa Cruze 1 Goat anti- Cat# SC-21248; human Lot# A2313 NESTIN Dispense type: 150 μL Step type: Reagent Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: Leica Microsystems 2 *BondWashSolution Dispense type: 150 μL Step type: Wash Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: Leica Microsystems 3 *BondWashSolution Dispense type: 150 μL Step type: Wash Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: Leica Microsystems 4 *BondWashSolution Dispense type: 150 μL Step type: Wash Step Reagent Inc. (min): 2:00 Temperature: Ambient Supplier: Leica Microsystems 5 *BondWashSolution Dispense type: 150 μL Step type: Wash Step Reagent Inc. (min): 2:00 Temperature: Ambient Supplier: Leica Microsystems 6 *BondWashSolution Dispense type: 150 μL Step type: Wash Step Reagent Inc. (min): 2:00 Temperature: Ambient Supplier: Leica Microsystems 7 *BondWashSolution Dispense type: 150 μL Step type: Wash Step Reagent Inc. (min): 8:00 Temperature: Ambient Supplier: VWR 8 TBS-t Cat# J640-1L Step type: Reagent Dispense type: 150 μL Step Reagent Inc. (min): 2.00 Temperature: Ambient Supplier: Leica Microsystems 9 *BondWashSolution Dispense type: 150 μL Step type: Wash Step Reagent Inc. (min): 2:00 Temperature: Ambient Supplier: Leica Microsystems 10 *BondWashSolution Dispense type: 150 μL Step type: Wash Step Reagent Inc. (min ): 2:00 Temperature: Ambient Supplier: Leica Microsystems 11 *BondWashSolution Dispense type: 150 μL Step type: Wash Step Reagent Inc. (min): 8:00 Temperature: Ambient Supplier: Leica Microsystems 12 *Polymer Dispense type: 150 μL Step type: Reagent Step Reagent Inc. (min): 2:00 Temperature: Ambient Supplier: Leica Microsystems 13 *BondWashSolution Dispense type: 150 μL Step type: Wash Step Reagent Inc. (min): 2.00 Temperature: Ambient Supplier: Leica Microsystems 14 *BondWashSolution Dispense type: 150 μL Step type: Wash Step Reagent Inc. (min): 2:00 Temperature: Ambient Supplier: Leica Microsystems 15 *BondWashSolution Dispense type: 150 μL Step type: Wash Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: Leica Microsystems 16 *BondWashSolution Dispense type: 150 μL Step type: Wash Step Reagent Inc. (min): 5:00 Temperature: Ambient Supplier: Leica Microsystems 17 *Peroxide Block Dispense type: 150 μL Step type: Reagent Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: Leica Microsystems 18 *BondWashSolution Dispense type: 150 μL Step type: Wash Step Reagent Inc. (min): 0.00 Temperature: Ambient Supplier: Leica Microsystems 19 *BondWashSolution Dispense type: Open Step type: Wash Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: Leica Microsystems 20 *BondWashSolution Dispense type: 150 μL Step type: Wash Step Reagent Inc. (min): 0.00 Temperature: Ambient Supplier: Notapplicable 21 *Deionized Water Dispense type: 150 μL Step type: Reagent Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: Notapplicable 22 *Deionized Water Dispense type: 150 μL Step type: Wash Step Reagent Inc. (min): 2:00 Temperature: Ambient Supplier: Leica Microsystems 23 *MixedDABRefine Dispense type: 150 μL Step type: Reagent Step Reagent IBC. (min): 5:00 Temperature: Ambient Supplier: Leica Microsystems 24 *MixedDABRefine Dispense type: 150 μL Step type: Reagent Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: Notapplicable 25 *Deionized Water Dispense type: 150 μL Step type: Wash Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: Notapplicable 26 *Deionized Water Dispense type: 150 μL Step type: Wash Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: Notapplicable 27 *Deionized Water Dispense type: 150 μL Step type: Wash Step Reagent Inc. (min): 10:00 Temperature: Ambient Supplier: Leica Microsystems 28 *Hematoxylin Dispense type: 150 μL Step type: Reagent Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: Leica Microsystems 29 *Deionized Water Dispense type: 150 μL Step type: Wash Step Reagent Inc. (min): 1:00 Temperature: Ambient Supplier: Leica Microsystems 30 *BondWashSolution Dispense type: 150 μL Step type: Wash Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: Leica Microsystems 31 *BondWashSolution Dispense type: 150 μL Step type: Wash Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: Notapplicable 32 *Deioniz ed Water Dispense type: 150 μL Step type: Wash -
TABLE C Step Reagent Inc. (min): 30:00 Temperature: Ambient Supplier: VWR 1 TBS-t Cat# J640-1L Step type: Reagent Dispense type: 150 μL Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: Leica Microsystems 2 *BondWashSolution Dispense type: 150 μL Step type: Wash Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: Leica Microsystems 3 *BondWashSolution Dispense type: 150 μL Step type: Wash Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: Leica Microsystems 4 *BondWashSolution Dispense type: 150 μL Step type: Wash Step Reagent Inc. (min): 2:00 Temperature: Ambient Supplier: Leica Microsystems 5 *BondWashSolution Dispense type: 150 μL Step type: Wash Step Reagent Inc. (min): 2:00 Temperature: Ambient Supplier: Leica Microsystems 6 *BondWashSolution Dispense type: 150 μL Step type: Wash Step Reagent Inc. (min): 2:00 Temperature: Ambient Supplier: Leica Microsystems 7 *BondWashSolution Dispense type: 150 μL Step type: Wash Step Reagent Inc. (min): 8:00 Temperature: Ambient Supplier: Vector Lab 8 Rabbit anti- Cat# BA-5000 goat IgG Dispense type: 150 μL Step type: Reagent Step Reagent Inc. (min): 2:00 Temperature: Ambient Supplier: Leica Microsystems 9 *BondWashSolution Dispense type: 150 μL Step type: Wash Step Reagent Inc. (min): 2:00 Temperature: Ambient Supplier: Leica Microsystems 10 *BondWashSolution Dispense type: 150 μL Step type: Wash Step Reagent Inc. (min): 2:00 Temperature: Ambient Supplier: Leica Microsystems 11 *BondWashSolution Dispense type: 150 μL Step type: Wash Step Reagent Inc. (min): 8:00 Temperature: Ambient Supplier: Leica Microsystems 12 *Polymer Dispense type: 150 μL Step type: Reagent Step Reagent Inc. (min): 2:00 Temperature: Ambient Supplier: Leica Microsystems 13 *BondWashSolution Dispense type: 150 μL Step type: Wash Step Reagent Inc. (min): 2:00 Temperature: Ambient Supplier: Leica Microsystems 14 *BondWashSolution Dispense type: 150 μL Step type: Wash Step Reagent Inc. (min): 2:00 Temperature: Ambient Supplier: Leica Microsystems 15 *BondWashSolution Dispense type: 150 μL Step type: Wash Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: Leica Microsystems 16 *BondWashSolution Dispense type: 150 μL Step type: Wash Step Reagent Inc. (min): 5:00 Temperature: Ambient Supplier: Leica Microsystems 17 *Peroxide Block Dispense type: 150 μL Step type: Reagent Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: Leica Microsystems 18 *BondWashSolution Dispense type: 150 μL Step type: Wash Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: Leica Microsystems 19 *BondWashSolution Dispense type: Open Step type: Wash Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: Leica Microsystems 20 *BondWashSolution Dispense type: 150 μL Step type: Wash Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: Notapplicable 21 *Deionized Water Dispense type: 150 μL Step type: Reagent Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: Notapplicable 22 *Deionized Water Dispense type: 150 μL Step type: Wash Step Reagent Inc. (min): 2:00 Temperature: Ambient Supplier: Leica Microsystems 23 *MixedDABRefine Dispense type: 150 μL Step type: Reagent Step Reagent Inc. (min): 5:00 Temperature: Ambient Supplier: Leica Microsystems 24 *MixedDABRefine Dispense type: 150 μL Step type: Reagent Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: Notapplicable 25 *Deionized Water Dispense type: 150 μL Step type: Wash Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: Notapplicable 26 *Deionized Water Dispense type: 150 μL Step type: Wash Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: Notapplicable 27 *Deionized Water Dispense type: 150 μL Step type: Wash Step Reagent Inc. (min): 10:00 Temperature: Ambient Supplier: Leica Microsystems 28 *Hematoxylin Dispense type: 150 μL Step type: Reagent Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: Notapplicable 29 *Deionized Water Dispense type: 150 μL Step type: Wash Step Reagent Inc. (min): 1:00 Temperature: Ambient Supplier: Leica Microsystems 30 *BondWashSolution Dispense type: 150 μL Step type: Wash Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: Leica Microsystems 31 *BondWashSolution Dispense type: 150 μL Step type: Wash Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: Notapplicable 32 *Deionized Water Dispense type: 150 μL Step type: Wash -
TABLE D Step Reagent Inc. (min): 30:00 Temperature: Ambient Supplier: SantaCruze, (Cat# SC-21248; 1 Goat anti- Lot# A2313) human Dispense type: 150 μL NESTIN Step type: Reagent Step Reagent Inc. (min): 2:00 Temperature: Ambient Supplier: Leica Microsystems 2 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 2:00 Temperature: Ambient Supplier: Leica Microsystems 3 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 2:00 Temperature: Ambient Supplier: Leica Microsystems 4 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: Leica Microsystems 5 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 8:00 Temperature: Ambient Supplier: Vector Lab (Cat# BA-5000) 6 Rabbit anti- Dispense type: 150 μL goat secondary antibody Step type: Reagent Step Reagent Inc. (min): 2:00 Temperature: Ambient Supplier: Leica Microsystems 7 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 2:00 Temperature: Ambient Supplier: Leica Microsystems 8 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 2:00 Temperature: Ambient Supplier: Leica Microsystems 9 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: Leica Microsystems 10 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 8:00 Temperature: Ambient Supplier: Bond Polymer Refine Detection kit 11 *Polymer Cat#: DS9800 Step type: Reagent Dispense type: 150 μL Step Reagent Inc. (min): 2:00 Temperature: Ambient Supplier: Leica Microsystems 12 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 2:00 Temperature: Ambient Supplier: Leica Microsystems 13 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 2:00 Temperature: Ambient Supplier: Leica Microsystems 14 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: Leica Microsystems 15 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 10:00 Temperature: Ambient Supplier: VWR 16 TBS-t Cat# J640-1L Step type: Reagent Dispense type: 150 μL Step Reagent Inc. (min): 2:00 Temperature: Ambient Supplier: Leica Microsystems 17 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 2:00 Temperature: Ambient Supplier: Leica Microsystems 18 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 2:00 Temperature: Ambient Supplier: Leica Microsystems 19 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: Leica Microsystems 20 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 0:00 Temperature: 100° C. Supplier: Perkin Elmer 21 AR9 Buffer Cat#AR900250ML Step type: Reagent Dispense type: 150 μL Step Reagent Inc. (min): 20:00 Temperature: 100° C. Supplier: Perkin Elmer 22 AR9 Buffer Cat#AR900250ML Step type: Reagent Dispense type: 150 μL Step Reagent Inc. (min): 0:00 Temperature: 100 Supplier: Perkin Elmer 23 AR9 Buffer Cat#AR900250ML Step type: Reagent Dispense type: 150 μL Step Reagent Inc. (min): 2:00 Temperature: Ambient Supplier: Perkin Elmer 24 AR9 Buffer Cat#AR900250ML Step type: Reagent Dispense type: 150 μL Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: Perkin Elmer 25 AR9 Buffer Cat#AR900250ML Step type: Reagent Dispense type: 150 μL Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: Leica Microsystems 26 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 10:00 Temperature: Ambient Supplier: Vector Lab 27 Normal horse serum Cat# MP-7402 kit Step type: Reagent Dispense type: 150 μL Step Reagent Inc. (min): 30:00 Temperature: Ambient Supplier: Creative BioLabs (2D12.5) 28 Mouse Cat# PABW-133 anti- Dispense type: 150 μL DOTA antibody 2D12.5 Step type: Reagent Step Reagent Inc. (min): 2:00 Temperature: Ambient Supplier: Leica Microsystems 29 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 2:00 Temperature: Ambient Supplier: Leica Microsystems 30 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 2:00 Temperature: Ambient Supplier: Leica Microsystems 31 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: Leica Microsystems 32 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 20:00 Temperature: Ambient Supplier: Vector Lab 33 Horse anti-mouse Cat# MP-7402 kit IgG Dispense type: 150 μL Step type: Reagent Step Reagent Inc. (min): 2:00 Temperature: Ambient Supplier: Leica Microsystems 34 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 2:00 Temperature: Ambient Supplier: Leica Microsystems 35 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 2:00 Temperature: Ambient Supplier: Leica Microsystems 36 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: Leica Microsystems 37 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 8:00 Temperature: Ambient Supplier: Bond Polymer Refine Detection kit 38 *Peroxide Block Cat# DS9800 Step type: Reagent Dispense type: 150 μL Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: Leica Microsystems 39 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: Leica Microsystems 40 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: Open Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: Leica Microsystems 41 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: B. BRAUN Medical Inc. #R5000-01 42 *Deionized Water Dispense type: 150 μL Step type: Reagent Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: B. BRAUN Medical Inc. #R5000-01 43 *Deionized Water Dispense type: 150 μL Step type: Wash Step Reagent Inc. (min): 2:00 Temperature: Ambient Supplier: Bond Polymer Refine Detection kit 44 *MixedDABRefine Cat# DS9800 Step type: Reagent Dispense type: 150 μL Step Reagent Inc. (min): 5:00 Temperature: Ambient Supplier: Bond Polymer Refine Detection kit 45 *MixedDABRefine Cat# DS9800 Step type: Reagent Dispense type: 150 μL Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: B. BRAUN Medical Inc. #R5000-01 46 *Deionized Water Dispense type: 150 μL Step type: Wash Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: B. BRAUN Medical Inc. #R5000-01 47 *Deionized Water Dispense type: 150 μL Step type: Wash Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: B. BRAUN Medical Inc. #R5000-01 48 *Deionized Water Dispense type: 150 μL Step type: Wash Step Reagent Inc. (min): 10:00 Temperature: Ambient Supplier: Bond Polymer Refine Detection kit 49 *Hematoxylin Cat# DS9800 Step type: Reagent Dispense type: 150 μL Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: B. BRAUN Medical Inc. #R5000-01 50 *Deionized Water Dispense type: 150 μL Step type: Wash Step Reagent Inc. (min): 1:00 Temperature: Ambient Supplier: Leica Microsystems 51 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: Leica Microsystems 52 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: B. BRAUN Medical Inc. #R5000-01 53 *Deionized Water Dispense type: 150 μL Step type: Wash -
TABLE E Step Reagent Inc. (min): 30:00 Temperature: Ambient Supplier: SantaCruze, (Cat# SC-21248; 1 Goat anti- Lot# A2313) human Dispense type: 150 μL NESTIN Step type: Reagent Step Reagent Inc. (min): 2:00 Temperature: Ambient Supplier: Leica Microsystems 2 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 2:00 Temperature: Ambient Supplier: Leica Microsystems 3 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 2:00 Temperature: Ambient Supplier: Leica Microsystems 4 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: Leica Microsystems 5 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 8:00 Temperature: Ambient Supplier: Vector Lab (Cat# BA-5000) 6 Rabbit anti- Dispense type: 150 0L goat secondary antibody Step type: Reagent Step Reagent Inc. (min): 2:00 Temperature: Ambient Supplier: Leica Microsystems 7 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 2:00 Temperature: Ambient Supplier: Leica Microsystems 8 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 2:00 Temperature: Ambient Supplier: Leica Microsystems 9 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: Leica Microsystems 10 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 8:00 Temperature: Ambient Supplier: Bond Polymer Refine Detection kit 11 *Polymer Cat# DS9800 Step type: Reagent Dispense type: 150 μL Step Reagent Inc. (min): 2:00 Temperature: Ambient Supplier: Leica Microsystems 12 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 2:00 Temperature: Ambient Supplier: Leica Microsystems 13 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 2:00 Temperature: Ambient Supplier: Leica Microsystems 14 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: Leica Microsystems 15 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 10:00 Temperature: Ambient Supplier: MSKCC 16 Compound Dispense type: 150 μL Step type: Reagent Step Reagent Inc. (min): 2:00 Temperature: Ambient Supplier: Leica Microsystems 17 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 2:00 Temperature: Ambient Supplier: Leica Microsystems 18 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 2:00 Temperature: Ambient Supplier: Leica Microsystems 19 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: Leica Microsystems 20 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 0:00 Temperature: 100° C. Supplier: Perkin Elmer 21 AR9 Buffer Cat# AR900250ML Step type: Reagent Dispense type: 150 μL Step Reagent Inc. (min): 20:00 Temperature: 100° C. Supplier: Perkin Elmer 22 AR9 Buffer Cat# AR900250ML Step type: Reagent Dispense type: 150 μL Step Reagent Inc. (min): 0:00 Temperature: 100 Supplier: Perkin Elmer 23 AR9 Buffer Cat# AR900250ML Step type: Reagent Dispense type: 150 μL Dispense type: 150 μL Step Reagent Cat#AR900250ML Supplier: Perkin Elmer 24 AR9 Buffer Inc. (min): 2:00 Temperature: Ambient Step type: Reagent Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: Perkin Elmer 25 AR9 Buffer Cat# AR900250ML Step type: Reagent Dispense type: 150 μL Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: Leica Microsystems 26 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 10:00 Temperature: Ambient Supplier: Vector Lab 27 Normal horse serum Cat# MP-7402 kit Step type: Reagent Dispense type: 150 μL 28 Mouse Inc. (min): 30:00 Temperature: Ambient Supplier: Creative Biolabs (2D12.5) anti- Cat# PABW-133 DOTA Dispense type: 150 μL antibody 2D12.5 Step type: Reagent Step Reagent Inc. (min): 2:00 Temperature: Ambient Supplier: Leica Microsystems 29 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 2:00 Temperature: Ambient Supplier: Leica Microsystems 30 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 2:00 Temperature: Ambient Supplier: Leica Microsystems 31 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: Leica Microsystems 32 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 20:00 Temperature: Ambient Supplier: Vector Lab 33 Horse anti-mouse Cat# MP-7402 kit IgG Dispense type: 150 μL Step type: Reagent Step Reagent Inc. (min): 2:00 Temperature: Ambient Supplier: Leica Microsystems 34 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 2:00 Temperature: Ambient Supplier: Leica Microsystems 35 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 2:00 Temperature: Ambient Supplier: Leica Microsystems 36 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: Leica Microsystems 37 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 8:00 Temperature: Ambient Supplier: Bond Polymer Refine Detection kit 38 *Peroxide Block Cat# DS9800 Step type: Reagent Dispense type: 150 μL Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: Leica Microsystems 39 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: Leica Microsystems 40 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: Open Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: Leica Microsystems 41 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: B. BRAUN Medical Inc. #R5000-01 42 *Deionized Water Dispense type: 150 μL Step type: Reagent Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: B. BRAUN Medical Inc. #R5000-01 43 *Deionized Water Dispense type: 150 μL Step type: Wash Step Reagent Inc. (min): 2:00 Temperature: Ambient Supplier: Bond Polymer Refine Detection kit 44 *MixedDABRefine Cat# DS9800 Step type: Reagent Dispense type: 150 μL Step Reagent Inc. (min): 5:00 Temperature: Ambient Supplier: Bond Polymer Refine Detection kit 45 *MixedDABRefine Cat# DS9800 Step type: Reagent Dispense type: 150 μL Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: B. BRAUN Medical Inc. #R5000-01 46 *Deionized Water Dispense type: 150 μL Step type: Wash Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: B. BRAUN Medical Inc. #R5000-01 47 *Deionized Water Dispense type: 150 μL Step type: Wash Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: B. BRAUN Medical Inc. #R5000-01 48 *Deionized Water Dispense type: 150 μL Step type: Wash Step Reagent Inc. (min): 10:00 Temperature: Ambient Supplier: Bond Polymer Refine Detection kit 49 *Hematoxylin Cat# DS9800 Step type: Reagent Dispense type: 150 μL Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: B. BRAUN Medical Inc. #R5000-01 50 *Deionized Water Dispense type: 150 μL Step type: Wash Step Reagent Inc. (min): 1:00 Temperature: Ambient Supplier: Leica Microsystems 51 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: Leica Microsystems 52 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: B. BRAUN Medical Inc. #R5000-01 53 *Deionized Water Dispense type: 150 μL Step type: Wash -
TABLE F Step Reagent Inc. (min): 30:00 Temperature: Ambient Supplier: SantaCruze, (Cat# SC-21248; 1 Goat anti- Lot# A2313) human Dispense type: 150 μL NESTIN Step type: Reagent Step Reagent Inc. (min): 2:00 Temperature: Ambient Supplier: Leica Microsystems 2 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 2:00 Temperature: Ambient Supplier: Leica Microsystems 3 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 2:00 Temperature: Ambient Supplier: Leica Microsystems 4 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: Leica Microsystems 5 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 8:00 Temperature: Ambient Supplier: Vector Lab (Cat# BA-5000) 6 Rabbit anti- Dispense type: 150 μL goat secondary antibody Step type: Reagent Step Reagent Inc. (min): 2:00 Temperature: Ambient Supplier: Leica Microsystems 7 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 2:00 Temperature: Ambient Supplier: Leica Microsystems 8 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 2:00 Temperature: Ambient Supplier: Leica Microsystems 9 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: Leica Microsystems 10 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 8:00 Temperature: Ambient Supplier: Bond Polymer Refine Detection kit 11 *Polymer Cat# DS9800 Step type: Reagent Dispense type: 150 μL Step Reagent Inc. (min): 2:00 Temperature: Ambient Supplier: Leica Microsystems 12 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 2:00 Temperature: Ambient Supplier: Leica Microsystems 13 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 2:00 Temperature: Ambient Supplier: Leica Microsystems 14 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: Leica Microsystems 15 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 10:00 Temperature: Ambient Supplier: MSKCC 16 Compound Dispense type: 150 μL Step type: Reagent Step Reagent Inc. (min): 2:00 Temperature: Ambient Supplier: Leica Microsystems 17 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 2:00 Temperature: Ambient Supplier: Leica Microsystems 18 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 2:00 Temperature: Ambient Supplier: Leica Microsystems 19 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: Leica Microsystems 20 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 0:00 Temperature: 100° C. Supplier: Perkin Elmer 21 AR9 Buffer Cat# AR900250ML Step type: Reagent Dispense type: 150 μL Step Reagent Inc. (min): 20:00 Temperature: 100° C. Supplier: Perkin Elmer 22 AR9 Buffer Cat# AR900250ML Step type: Reagent Dispense type: 150 μL Step Reagent Inc. (min): 0:00 Temperature: 100 Supplier: Perkin Elmer 23 AR9 Buffer Cat# AR900250ML Step type: Reagent Dispense type: 150 μL Step Reagent Inc. (min): 2:00 Temperature: Ambient Supplier: Perkin Elmer 24 AR9 Buffer Cat#AR900250ML Step type: Reagent Dispense type: 150 μL Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: Perkin Elmer 25 AR9 Buffer Cat# AR900250ML Step type: Reagent Dispense type: 150 μL Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: Leica Microsystems 26 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 10:00 Temperature: Ambient Supplier: Vector Lab 27 Normal horse serum Cat# MP-7402 kit Step type: Reagent Dispense type: 150 μL Step Reagent Inc. (min): 30:00 Temperature: Ambient Supplier: VWR 28 TBS-t Cat# J640-1L Step type: Reagent Dispense type: 150 μL Step Reagent Inc. (min): 2:00 Temperature: Ambient Supplier: Leica Microsystems 29 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 2:00 Temperature: Ambient Supplier: Leica Microsystems 30 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 2:00 Temperature: Ambient Supplier: Leica Microsystems 31 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: Leica Microsystems 32 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 20:00 Temperature: Ambient Supplier: Vector Lab 33 Horse anti-mouse Cat# MP-7402 kit IgG Dispense type: 150 μL Step type: Reagent Step Reagent Inc. (min): 2:00 Temperature: Ambient Supplier: Leica Microsystems 34 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 2:00 Temperature: Ambient Supplier: Leica Microsystems 35 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 2:00 Temperature: Ambient Supplier: Leica Microsystems 36 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: Leica Microsystems 37 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 8:00 Temperature: Ambient Supplier: Bond Polymer Refine Detection kit 38 *Peroxide Block Cat# DS9800 Step type: Reagent Dispense type: 150 μL Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: Leica Microsystems 39 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: Leica Microsystems 40 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: Leica Microsystems 41 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: B. BRAUN Medical Inc. #R5000-01 42 *Deionized Water Dispense type: 150 μL Step type: Reagent Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: B. BRAUN Medical Inc. #R5000-01 43 *Deionized Water Dispense type: 150 μL Step type: Wash Step Reagent Inc. (min): 2:00 Temperature: Ambient Supplier: Bond Polymer Refine Detection kit 44 *MixedDABRefine Cat# DS9800 Step type: Reagent Dispense type: 150 μL Step Reagent Inc. (min): 5:00 Temperature: Ambient Supplier: Bond Polymer Refine Detection kit 45 *MixedDABRefine Cat# DS9800 Step type: Reagent Dispense type: 150 μL Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: B. BRAUN Medical Inc. #R5000-01 46 *Deionized Water Dispense type: 150 μL Step type: Wash Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: B. BRAUN Medical Inc. #R5000-01 47 *Deionized Water Dispense type: 150 μL Step type: Wash Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: B. BRAUN Medical Inc. #R5000-01 48 *Deionized Water Dispense type: 150 μL Step type: Wash Step Reagent Inc. (min): 10:00 Temperature: Ambient Supplier: Bond Polymer Refine Detection kit 49 *Hematoxylin Step type: Reagent Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: B. BRAUN Medical Inc. #R5000-01 50 *Deionized Water Dispense type: 150 μL Step type: Wash Step Reagent Inc. (min): 1:00 Temperature: Ambient Supplier: Leica Microsystems 51 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: Leica Microsystems 52 *BondWashSolution Cat# AR9590 Step type: Wash Dispense type: 150 μL Step Reagent Inc. (min): 0:00 Temperature: Ambient Supplier: B. BRAUN Medical Inc. #R5000-01 53 *Deionized Water Dispense type: 150 μL Step type: Wash - In the claims articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.
- Furthermore, the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the invention, or aspects of the invention, is/are referred to as comprising particular elements and/or features, certain embodiments of the invention or aspects of the invention consist, or consist essentially of, such elements and/or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted that the terms “comprising” and “containing” are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub-range within the stated ranges in different embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise. This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present invention that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the invention can be excluded from any claim, for any reason, whether or not related to the existence of prior art.
- Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present invention, as defined in the following claims.
Claims (56)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US17/251,038 US20210188787A1 (en) | 2018-06-13 | 2019-06-13 | Dota compounds and uses thereof |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201862684573P | 2018-06-13 | 2018-06-13 | |
US17/251,038 US20210188787A1 (en) | 2018-06-13 | 2019-06-13 | Dota compounds and uses thereof |
PCT/US2019/037100 WO2019241594A1 (en) | 2018-06-13 | 2019-06-13 | Dota compounds and uses thereof |
Publications (1)
Publication Number | Publication Date |
---|---|
US20210188787A1 true US20210188787A1 (en) | 2021-06-24 |
Family
ID=68841875
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US17/251,038 Pending US20210188787A1 (en) | 2018-06-13 | 2019-06-13 | Dota compounds and uses thereof |
Country Status (4)
Country | Link |
---|---|
US (1) | US20210188787A1 (en) |
EP (1) | EP3806844A4 (en) |
CA (1) | CA3103637A1 (en) |
WO (1) | WO2019241594A1 (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2023003408A1 (en) * | 2021-07-21 | 2023-01-26 | 경북대학교 산학협력단 | Gadolinium-based compound and mri contrast agent including same |
WO2023003409A1 (en) * | 2021-07-21 | 2023-01-26 | 경북대학교 산학협력단 | Gadolinium-based compound and mri contrast agent comprising same |
KR20230014656A (en) * | 2021-07-21 | 2023-01-30 | 경북대학교 산학협력단 | Gadolinium-based compound, mri contrast agent comprising the same |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5196306A (en) | 1989-03-29 | 1993-03-23 | E. I. Du Pont De Nemours And Company | Method for the detection or quantitation of an analyte using an analyte dependent enzyme activation system |
AU2003270347B2 (en) | 2002-09-06 | 2007-05-24 | The Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services | Backbone-substituted bifunctional dota ligands, complexes and compositions thereof, and methods of using same |
WO2006014530A2 (en) | 2004-07-07 | 2006-02-09 | The General Hospital Corporation | Imaging of enzyme activity |
US9291597B2 (en) * | 2010-07-02 | 2016-03-22 | Ventana Medical Systems, Inc. | Detecting targets using mass tags and mass spectrometry |
-
2019
- 2019-06-13 CA CA3103637A patent/CA3103637A1/en active Pending
- 2019-06-13 EP EP19819617.2A patent/EP3806844A4/en active Pending
- 2019-06-13 US US17/251,038 patent/US20210188787A1/en active Pending
- 2019-06-13 WO PCT/US2019/037100 patent/WO2019241594A1/en unknown
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2023003408A1 (en) * | 2021-07-21 | 2023-01-26 | 경북대학교 산학협력단 | Gadolinium-based compound and mri contrast agent including same |
WO2023003409A1 (en) * | 2021-07-21 | 2023-01-26 | 경북대학교 산학협력단 | Gadolinium-based compound and mri contrast agent comprising same |
KR20230014656A (en) * | 2021-07-21 | 2023-01-30 | 경북대학교 산학협력단 | Gadolinium-based compound, mri contrast agent comprising the same |
KR102646267B1 (en) | 2021-07-21 | 2024-03-11 | 경북대학교 산학협력단 | Gadolinium-based compound, mri contrast agent comprising the same |
Also Published As
Publication number | Publication date |
---|---|
WO2019241594A8 (en) | 2020-01-09 |
EP3806844A4 (en) | 2022-03-09 |
CA3103637A1 (en) | 2019-12-19 |
EP3806844A1 (en) | 2021-04-21 |
WO2019241594A1 (en) | 2019-12-19 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US9547009B2 (en) | Benzocyclooctyne compounds and uses thereof | |
US20190000860A1 (en) | Use of compositions modulating chromatin structure for graft versus host disease (gvhd) | |
US11498892B2 (en) | Fe/Cu-mediated ketone synthesis | |
US11248007B2 (en) | Inhibitors of MALT1 and uses thereof | |
US20210188787A1 (en) | Dota compounds and uses thereof | |
US20230167081A1 (en) | 5-amino-2-piperidinon-3-yl-1-oxoisoindoline derivatives for degradation of ikzf2 degraders | |
US10106833B2 (en) | Methods and compounds for identifying glycosyltransferase inhibitors | |
US10100081B2 (en) | Trapping reagents for reactive metabolites screening | |
US9902985B2 (en) | Chemoenzymatic methods for synthesizing moenomycin analogs | |
US11028055B2 (en) | Compounds for treating proliferative diseases | |
US20230028318A1 (en) | Fluorogenic amino acids | |
US20230135188A1 (en) | Fe/cu-mediated ketone synthesis | |
US20230357286A1 (en) | Ketone synthesis and applications | |
US20230391799A1 (en) | Fluorescent dye for protein or nucleic acid labelling | |
WO2023196605A1 (en) | Inhibiting histone deacetylase 6 (hdac6) | |
WO2023064345A1 (en) | Small molecule modulators of glucocerebrosidase activity and uses thereof | |
EP4329880A1 (en) | Small molecule modulators of glucocerebrosidase activity and uses thereof | |
WO2023150203A1 (en) | Hdac6 inhibitors and uses thereof | |
WO2024059107A1 (en) | Ikzf2 and ck1-alpha degrading compounds and uses thereof | |
WO2023230308A1 (en) | DEGRADER COMPOUNDS OF QSOX1 mRNA | |
WO2023250342A2 (en) | Cyclopropene phosphoramidites and conjugates thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: MEMORIAL SLOAN-KETTERING CANCER CENTER, NEW YORK Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:OUERFELLI, OUATHEK;YANG, GUANGBIN;HOLLMANN, TRAVIS JASON;SIGNING DATES FROM 20200414 TO 20200415;REEL/FRAME:055812/0768 |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: APPLICATION DISPATCHED FROM PREEXAM, NOT YET DOCKETED |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: DOCKETED NEW CASE - READY FOR EXAMINATION |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: NON FINAL ACTION MAILED |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: RESPONSE TO NON-FINAL OFFICE ACTION ENTERED AND FORWARDED TO EXAMINER |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: NON FINAL ACTION MAILED |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: RESPONSE TO NON-FINAL OFFICE ACTION ENTERED AND FORWARDED TO EXAMINER |